Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naïve (AMBER) and virologically suppressed (EMERALD) participants with neurological and/or psychiatric comorbidities: Week 96 subgroup analysis.

OBJECTIVE: Our objective was to evaluate the prevalence of pre-existing neurological and/or psychiatric comorbidities (NPCs) and efficacy/safety outcomes for participants with versus without baseline NPCs in AMBER and EMERALD. METHODS: AMBER (treatment-naïve population) and EMERALD (virologically suppressed population) were phase III randomized studies of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg. The primary objective of this post hoc analysis was to assess virological response (HIV-1 RNA <50 copies/mL) at week 48 by intent-to-treat US Food and Drug Administration snapshot analysis comparing participants with and without baseline NPCs. RESULTS: Among participants in AMBER, 88/362 (24%) in the D/C/F/TAF arm and 99/363 (27%) in the control arm had baseline NPCs; in EMERALD, 294/763 (39%; D/C/F/TAF) and 166/378 (44%; control) participants had baseline NPCs. At baseline, psychiatric NPCs were more common than neurological NPCs in both studies; the most common of each type were depression and headache, respectively. High virological response rates were achieved with D/C/F/TAF across studies regardless of baseline NPCs at weeks 48 (range 86%-95%) and 96 (range 80%-91%). No participants in either study with a baseline NPC prematurely discontinued because of a study drug-related neurological or psychiatric adverse event. CONCLUSION: D/C/F/TAF may be a suitable treatment option for individuals with HIV-1 and NPCs.

Low Incidence and Brief Duration of Gastrointestinal Adverse Events with Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Over 96 Weeks: Post hoc Analyses of AMBER and EMERALD.

Gastrointestinal intolerance has been associated with ritonavir-boosted protease inhibitors. This post hoc analysis evaluated gastrointestinal adverse events of interest (AEOIs; diarrhea, nausea, abdominal discomfort, flatulence [MedDRAv21]) through Wk96 among patients enrolled in the phase 3 AMBER (treatment-naïve) and EMERALD (virologically suppressed) studies of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg. 362 and 763 patients initiated D/C/F/TAF in AMBER and EMERALD, respectively. All D/C/F/TAF-related gastrointestinal AEOIs were grade 1/2 in severity; none were serious. Across studies, incidence of D/C/F/TAF-related diarrhea and nausea were each ≤5% in Wk1 (≤1% post-Wk2); prevalence of each decreased to <5% post-Wk2. In each study, there was 1 case of D/C/F/TAF-related abdominal discomfort during Wk1 and none thereafter. Incidence of D/C/F/TAF-related flatulence was <1% throughout. Median duration of D/C/F/TAF-related gastrointestinal AEOIs was 16.5 (AMBER) and 8.5 (EMERALD) days. In conclusion, in treatment-naïve and virologically suppressed patients, incidences and prevalences of D/C/F/TAF-related gastrointestinal AEOIs were low and tended to present early.

Weight Change and Predictors of Weight Change Among Patients Initiated on Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide or Bictegravir/Emtricitabine/Tenofovir Alafenamide: A Real-World Retrospective Study.

Background: Recent evidence suggests that integrase strand transfer inhibitors are associated with greater weight gain than protease inhibitors in patients with human immunodeficiency virus (HIV-1). Objectives: To describe demographic and clinical characteristics of insured patients with HIV-1 in the United States initiating darunavir/​cobicistat/​emtricitabine/​tenofovir alafenamide (DRV/c/FTC/TAF) or bictegravir/FTC/TAF (BIC/FTC/TAF), assess the differences in weight and body mass index (BMI) change between cohorts up to one year after treatment initiation, and identify the predictors of weight gain associated with each treatment. Methods: The Symphony Health, IDV® database (July 17, 2017 - September 30, 2019) was used to identify treatment naïve or virologically suppressed stable switchers who initiated DRV/c/FTC/TAF or BIC/FTC/TAF (index date) on or after July 17, 2018, were ≥18 years of age on the index date, and had ≥12 months of continuous clinical activity pre-index (baseline period). To account for differences in baseline characteristics, inverse-probability of treatment weighting (IPTW) was used. Mean weight and BMI change from pre- to post-index measurements were compared between weighted cohorts at 3, 6, 9, and 12 months post-index using mean differences. Predictors of weight or BMI gain ≥5% were evaluated at last measurement, for each treatment cohort separately. Results: After IPTW, 452 and 497 patients were included in the DRV/c/FTC/TAF and BIC/FTC/TAF cohorts, respectively. Baseline characteristics were generally well-balanced (mean age=~50 years, female: ~30%), except for the type of antiretroviral therapy from which patients switched. Patients initiated on BIC/FTC/TAF experienced greater weight and BMI increases between the pre-index period and each measurement of the post-index period than patients initiated on DRV/c/FTC/TAF, although results were only statistically significant at 9 months post-index (weight: mean difference=2.50 kg, P=0.005; BMI: mean difference=0.66 kg/m2, P=0.027). A common predictor of weight or BMI gain ≥5% among patients in both cohorts was female gender (DRV/c/FTC/TAF: odds ratio [OR]=5.92, P=0.014; BIC/FTC/TAF: OR=2.00, P<0.001). Conclusion: Patients in the BIC/FTC/TAF cohort experienced greater weight and BMI increases than patients in the DRV/c/FTC/TAF cohort, with differences reaching statistical significance at 9 months post-index. Weight gain is an important factor to consider when selecting antiretroviral regimens, since it is associated with long-term health consequences. Future studies with larger sample size and longer follow-up time are warranted.

Rapid initiation of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in acute and early HIV-1 infection: a DIAMOND subgroup analysis.

BACKGROUND: Treatment during acute or early human immunodeficiency virus (HIV)-1 infection is associated with immunologic and virologic benefits. OBJECTIVE: To evaluate darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) efficacy/safety among patients with acute or early HIV-1 infection who rapidly initiate treatment. METHODS: DIAMOND (ClinicalTrials.gov Identifier: NCT03227861), a phase 3 study, evaluated the efficacy/safety of D/C/F/TAF 800/150/200/10 mg in rapid initiation. Adults aged ≥18 years began D/C/F/TAF within 14 days of diagnosis, prior to the availability of screening/baseline laboratory results. In this subgroup analysis, virologic response (HIV-1 RNA <50 copies/mL) was assessed at Week 48 by intent-to-treat FDA snapshot (ITT-FDA snapshot) and observed (excluding patients with missing data) analyses in patients with acute (HIV-1 antibody negative and HIV-1 RNA positive/p24 positive) or early (HIV-1 antibody positive and suspected infection ≤6 months before screening/baseline) infection. RESULTS: Among 109 patients, 13 had acute and 43 had early HIV-1 infection. High rates of virologic response were demonstrated at Week 48 by ITT-FDA snapshot (acute: 10/13 [76.9%]; early: 37/43 [86.0%]) and observed (acute: 10/11 [90.9%]; early: 37/38 [97.4%]) analyses. No patients discontinued or required regimen change due to baseline resistance or lack of efficacy, or developed protocol-defined virologic failure. Through Week 48, 7 (53.8%) acute and 22 (51.2%) early infection patients had a D/C/F/TAF-related adverse event (AE); none had a D/C/F/TAF-related grade 4 or serious AE. CONCLUSIONS: High rates of viral suppression during acute/early infection were achieved with D/C/F/TAF rapid initiation, no treatment-emergent resistant mutations were observed, and D/C/F/TAF was safe and well tolerated.

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in a Rapid-Initiation Model of Care for Human Immunodeficiency Virus Type 1 Infection: Primary Analysis of the DIAMOND Study.

BACKGROUND: Most guidelines recommend rapid treatment initiation for patients with newly diagnosed human immunodeficiency virus type 1 (HIV-1) infection, but prospective US data are limited. The DIAMOND (NCT03227861) study using darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a phase 3 prospective study evaluating efficacy/safety of a single-tablet regimen in a rapid-initiation model of care. METHODS: Adults aged ≥18 years began D/C/F/TAF ≤14 days from diagnosis without screening/baseline results; as results became available, participants not meeting predefined safety/resistance stopping rules continued. Primary endpoint was virologic response (HIV-1 RNA <50 copies/mL; intent-to-treat; US Food and Drug Administration [FDA] snapshot) at week 48; participant satisfaction was measured via the HIV Treatment Satisfaction Questionnaire status version (HIVTSQs). RESULTS: Of 109 participants, 87% were male, 32% black/African American, median (range) age was 28 (range, 19-66) years, 25% of participants had HIV-1 RNA ≥100 000 copies/mL, 21% had CD4+ cell count <200 cells/µL, and 31% enrolled ≤48 hours from diagnosis. At week 48, 97 (89%) participants completed the study and 92 (84%) achieved HIV-1 RNA <50 copies/mL (FDA snapshot). There were no protocol-defined virologic failures; incidences of adverse events (AEs) and adverse drug reactions (33%) were low, no serious AEs were study drug related, and 1 (<1%) participant discontinued due to study drug related AE(s). The overall HIVTSQs score at week 48 was 58 (maximum: 60). CONCLUSIONS: At week 48, a high proportion of participants starting D/C/F/TAF achieved HIV-1 RNA <50 copies/mL and very few discontinued therapy. D/C/F/TAF was well tolerated, no participants discontinued due to baseline resistance stopping criteria, and high treatment satisfaction among participants was recorded. CLINICAL TRIALS REGISTRATION: NCT03227861.

Long-Term Benefits of Rapid Antiretroviral Therapy Initiation in Reducing Medical and Overall Health Care Costs Among Medicaid-Covered Patients with Human Immunodeficiency Virus.

BACKGROUND: New guidelines for the treatment of human immunodeficiency virus (HIV) suggest that morbidity and mortality could be reduced if antiretroviral therapy (ART) was initiated immediately after diagnosis, regardless of CD4 cell count. OBJECTIVE: To assess real-world time to ART initiation and describe medical, pharmacy, and total health care costs in the 6-, 12-, 24-, and 36-month periods after HIV diagnosis based on time to ART initiation among Medicaid-covered patients. METHODS: Multistate Medicaid data (January 2012-March 2017) was used to identify adults with HIV-1 initiating ART ≤ 360 days of initial HIV-1 diagnosis. People living with HIV (PLWH) were sorted into mutually exclusive cohorts based on time from diagnosis to ART initiation (≤ 14 days, > 14 to ≤ 60 days, > 60 to ≤ 180 days, and > 180 to ≤ 360 days). ART regimen had to include a protease inhibitor, an integrase strand transfer inhibitor, or a non-nucleoside reverse transcriptase inhibitor, with ≥ 2 nucleoside reverse transcriptase inhibitors. Medical, pharmacy, and total health care costs in the 6, 12, 24, and 36 months following HIV diagnosis were stratified by timeliness of ART initiation. RESULTS: Of 974 patients, 347 (35.6%) initiated ART > 360 days after diagnosis and were excluded. Among the remaining 627 eligible patients, mean age was 39.9 years, 42.7% were female, and 53.9% were black. Among them, 128 (20.4%) were treated ≤ 14 days, 228 (36.4%) between > 14 and ≤ 60 days, 163 (26.0%) between > 60 and ≤ 180 days, and 108 (17.2%) between > 180 and ≤ 360 days. Among patients treated ≤ 180 days, 4.6% had ≥ 1 opportunistic infection in the 6-month period before ART initiation; this proportion reached 5.6% for patients treated >180 and ≤ 360 days. Over the 6-, 12-, 24-, and 36-month periods after diagnosis, per-patient-per-month (PPPM) medical costs were lower for patients who initiated ART ≤ 14 days than for those who initiated > 180 and ≤ 360 days after diagnosis (6 months: $1,611 [≤ 14 days] vs. $3,008 [> 180 and ≤ 360 days]; 12 months: $1,188 vs. $2,110; 24 months: $754 vs. $1,368; 36 months: $651 vs. $1,196). Over the same periods, medical costs generally accounted for > 50% of total health care costs for patients who initiated ART between > 60 and ≤ 180 days and > 180 and ≤ 360 days and for 30%-40% of total health care costs for patients treated ≤ 14 days and between > 14 and ≤ 60 days. Total PPPM health care costs increased with delay of ART initiation in the 36-month period after diagnosis ($2,058 [treated ≤ 14 days] vs. $2,310 [treated between > 180 and ≤ 360 days]). CONCLUSIONS: In this study from 2012 to 2017 of Medicaid PLWH treated with ART, 20.4% initiated ART ≤14 days of HIV diagnosis. Patients with delayed ART initiation accumulated more total health care costs in the 36-month period after HIV diagnosis than those initiated within 14 days, highlighting the long-term benefit of rapid ART initiation. An important opportunity remains to engage PLWH in care more rapidly. DISCLOSURES: This study was supported by Janssen Scientific Affairs, which was involved in the study design, interpretation of results, manuscript preparation, and publication decisions. Emond, Romdhani, Lefebvre, and Côté-Sergent are employees of Analysis Group, a consulting company that was contracted by Janssen Scientific Affairs to conduct this study and develop the manuscript. Shohoudi was an employee of Analysis Group at the time the study was conducted. Benson, Tandon, Chow, and Dunn are employees and stockholders of Johnson & Johnson. Parts of the material in this study have been presented at the HIV Drug Therapy Meeting; October 28-31, 2018; Glasgow, UK, and the AMCP Annual Meeting; March 25-28, 2019; San Diego, CA.

Rapid Initiation of Antiretroviral Therapy Following Diagnosis of Human Immunodeficiency Virus Among Patients with Commercial Insurance Coverage.

BACKGROUND: New guidelines for the treatment of human immunodeficiency virus (HIV) advocate for rapid initiation of antiretroviral therapy (ART) ≤ 7 days after HIV diagnosis with agents that have a high genetic barrier to resistance, good tolerability, and convenient dosing. OBJECTIVE: To describe characteristics, time to ART initiation, and health care costs in commercially insured patients living with HIV in the United States who are treated ≤ 60 days after HIV diagnosis. METHODS: IBM MarketScan Research Databases (January 1, 2012-December 31, 2017) were used to identify ART-naive adults with HIV-1, ≥ 6 months of continuous eligibility before first HIV diagnosis, and ART initiation ≤ 60 days of first diagnosis. ART regimen had to include a protease inhibitor (PI), an integrase strand transfer inhibitor (INSTI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) with ≥ 2 nucleoside reverse transcriptase inhibitors. Cohorts were formed based on time to ART initiation after diagnosis: ≤ 7 days or 8-60 days. Health care costs were evaluated at 6, 12, 24, and 36 months after diagnosis among patients with ≥ 36 months of continuous eligibility. RESULTS: Among 9,351 patients, median time to treatment was 31.0 days. Patients initiating ART > 60 days after HIV diagnosis were excluded (N = 2,608 [27.9%]), while 6,743 (72.1%) initiated ART ≤ 60 days after diagnosis and were analyzed; 18.3% and 81.7% were classified in the ≤ 7 days and 8-60 days cohorts, respectively. For all analyzed patients, mean age was 38.0 (SD = 12.0) years and 13.2% were female; 12.7%, 56.2%, and 31.1% initiated a PI, INSTI, or NNRTI-based regimen, respectively. Elvitegravir (32.9%), efavirenz (20.9%), dolutegravir (18.5%), and darunavir (8.5%) were the most commonly used antiretrovirals; most patients (74.3%) were initiated on single-tablet regimens. PI-based regimens were more common in the ≤ 7 days cohort (PI = 18.1%; darunavir = 11.4%) than in the 8-60 days cohort (PI = 11.5%; darunavir = 7.8%). INSTI-based regimens were more common in the 8-60 days cohort (INSTI = 57.7%; elvitegravir = 33.8%) than in the ≤ 7 days cohort (INSTI = 49.2%; elvitegravir = 29.1%). NNRTI-based regimens were as common in the ≤ 7 days (32.7%) and 8-60 days (30.7%) cohorts. Mean total accumulated costs were lower among patients in the ≤ 7 days cohort than in the 8-60 days cohort at all time points analyzed after diagnosis (e.g., 36 months: ≤ 7 days = $109,456; 8-60 days = $116,870). Total per-patient per-month costs decreased over time in the ≤ 7 days (i.e., 6 months = $4,359; 36 months = $3,040) and 8-60 days cohort (6 months = $4,727; 36 months = $3,246). CONCLUSIONS: Although 72.1% of patients initiated ART ≤ 60 days after HIV diagnosis, only 18.3% initiated ART ≤ 7 days. Many patients initiating ART ≤ 7 days used suboptimal agents with low rather than high genetic barriers to resistance (i.e., efavirenz and elvitegravir) or agents (dolutegravir) coformulated with other antiretrovirals that require testing to prevent hypersensitivity reactions. Patients in the ≤ 7 days cohort showed lower total health care costs relative to those in the 8-60 days cohort, highlighting the potential long-term benefits of rapid ART initiation. DISCLOSURES: This study was supported by Janssen Scientific Affairs, which was involved in the study design, interpretation of results, manuscript preparation, and publication decisions. Emond, Lefebvre, Lafeuille, and Côté-Sergent are employees of Analysis Group, a consulting company that was contracted by Janssen Scientific Affairs to conduct this study and develop the manuscript. Benson, Tandon, Chow, and Dunn are employees of Janssen Scientific Affairs and stockholders of Johnson & Johnson. Part of the material in this study has been presented at the AMCP 2019 Annual Meeting; March 25-28, 2019; San Diego, CA.

Trends in HIV-1 Drug Resistance Mutations from a U.S. Reference Laboratory from 2006 to 2017.

Trends in resistance to antiretroviral drugs for HIV-1 may inform clinical support and drug development. We evaluated drug resistance mutation (DRM) trends for nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), and integrase strand transfer inhibitor (INSTI) in a large U.S. reference laboratory database. DRMs with a Stanford HIV Drug Resistance Database mutation score ≥10 from deidentified subtype B NRTI/NNRTI/PI specimens (2006-2017; >10,000/year) and INSTI specimens (2010-2017; >1,000/year) were evaluated. Sequences with NRTI, NNRTI, or PI single- or multiclass DRMs declined from 48.9% to 39.3%. High-level dual- and triple-class resistance declined from 43.3% (2006) to 17.1% (2017), while sequences with only single-class DRMs increased from 40.0% to 52.9%. The prevalence of DRMs associated with earlier treatment regimens declined, while prevalence of some DRMs associated with newer regimens increased. M184V/I decreased from 48.3% to 29.4%. K103N/S/T declined from 42.5% in 2012 to 36.4% in 2017. Rilpivirine and etravirine DRMs E138A/Q/R and E138K increased from 4.9% and 0.4% to 9.7% and 1.7%, respectively. Sequences with ≥1 darunavir DRM declined from 18.1% to 4.8% by 2017. INSTI DRM Q148H/K/R declined from 39.3% (2010) to 13.8% (2017). Prevalence of elvitegravir-associated DRMs T66A/I/K, E92Q, S147G, and the dolutegravir-associated DRM R263K increased. For a subset of patients with serial testing, 50% (2,646/5,290) of those who initially had no reportable DRM subsequently developed ≥1 DRM for NRTI/NNRTI/PI and 49.7% (159/320) for INSTI. These trends may inform the need for baseline genotypic resistance testing. The detection of treatment-emergent DRMs in serially tested patients confirms the value of genotypic testing following virologic failure.

Risk Factors, Health Care Resource Utilization, and Costs Associated with Nonadherence to Antiretrovirals in Medicaid-Insured Patients with HIV.

BACKGROUND: Adherence to antiretrovirals (ARVs) is critical to achieving durable virologic suppression. OBJECTIVE: To investigate risk factors of poor adherence and the effect of suboptimal adherence on health care resource utilization (HCRU) and costs in Medicaid patients. METHODS: A retrospective longitudinal study was conducted using Medicaid data. Adults (aged ≥ 18 years) with human immunodeficiency virus (HIV)-1 initiating selected ARVs (index date) were identified. Adherence was measured using medication possession ratio (MPR) and proportion of days covered (PDC) at 6 and 12 months post-index. Risk factors of poor adherence (PDC < 80%) were assessed using a logistic regression. HCRU and costs were compared between suboptimal (80% ≤ PDC < 95%) and optimal (PDC ≥ 95%) adherence groups using Poisson and ordinary least square models, respectively. RESULTS: In total, 3,477 patients were identified. Using MPR, 1,282 (39.0%) of the evaluable patients had poor adherence; 667 (20.2%) had suboptimal adherence; and 1,342 (40.8%) had optimal adherence versus 1,342 (51.1%), 509 (19.0%), and 804 (30.0%), respectively, using PDC at 6 months. PDC at 12 months was even lower. Younger age (OR = 1.58; 95% CI = 1.18-2.11; P = 0.002), noncapitated coverage (OR = 1.40; 95% CI = 1.16-1.69; P < 0.001), dual Medicaid/Medicare coverage (OR = 5.98; 95% CI = 4.39-8.16; P < 0.001), no baseline ARV treatment (OR = 1.98; 95% CI = 1.62-2.41; P < 0.001), and baseline asymptomatic HIV (OR = 1.37; 95% CI = 1.13-1.68; P = 0.002) were associated with higher risk of poor adherence. Suboptimal adherence patients had higher total number of days spent in a hospital (incidence rate ratio [IRR] = 1.62; 95% CI = 1.13-2.19; P = 0.008), total number of long-term care admissions (IRR = 3.11; 95% CI = 1.26-7.39; P = 0.008), total medical costs (mean monthly cost difference = $339; 95% CI = $153-$536; P < 0.001), and inpatient costs (mean monthly cost difference = $259; 95% CI = $122-$418; P < 0.001) compared with patients with optimal adherence. CONCLUSIONS: Nonadherence to ARVs was observed in 60%-80% of Medicaid patients, depending on the adherence measure used, and was associated with incremental HCRU and costs. Age, insurance type and coverage, previous ARV treatment, and HIV symptoms were predictors of adherence. Treatment options that enhance adherence and prevent developing virologic failure with drug resistance should be considered for HIV patients. DISCLOSURES: This study was supported by Janssen Scientific Affairs, which was involved in the study design, data collection, data analysis, manuscript preparation, and publication decisions. Emond, Lafeuille, Romdhani, and Lefebvre are employees of Analysis Group, a consulting company that received research grants from Janssen Scientific Affairs to conduct this study. Dunn, Woodruff, Pesa, and Tandon are current employees and stockholders of Johnson & Johnson, owner of Janssen Scientific Affairs. Jiao was an employee of Janssen at the time of the study. Emond has received grants from Novartis, Regeneron, Aegerion, Lundbeck, Bristol-Myers Squibb, Bayer, Millennium, Allergan, AbbVie, and GlaxoSmithKline unrelated to this study. Part of the material in this study was presented at the Academy of Managed Care Pharmacy 2017 Annual Meeting; March 27-30, 2017; Denver, CO, and at the 9th International AIDS Society Conference; July 23-26, 2017; Paris, France.