Faculty Bibliography

Introduction/UNASSIGNED:A comprehensive assessment of liver disorders was conducted among people living with HIV (PLWH) on a new antiretroviral regimen based on common core agents. Methods/UNASSIGNED:cohort were included if they had ⩾1 liver chemistry test performed both within 12 months before regimen start and over follow-up. Liver disorders were defined as a diagnosis of drug-induced liver injury (DILI) or moderate/severe liver chemistry elevations (LCE). History of liver disorders experienced within 12 months of initiation was summarized. Liver disorders occurring during follow-up were described as prevalent (all disorders) or incident (disorders occurring among PLWH without a history of liver disorders or advanced liver fibrosis). Results/UNASSIGNED:Out of 16,024 PLWH, 38% initiated DTG, 43% EVG, 5% RAL, and 14% DRV. EVG users were younger and had a lower likelihood of comorbidities or lipid-lowering agent use than DTG users. EVG users were significantly less likely to have a history of moderate/severe LCE or to have prevalent moderate LCE. RAL users were older and had a higher likelihood of comorbidities or lipid-lowering agent use than DTG users. RAL users were significantly more likely to have a history of advanced liver fibrosis and prevalent moderate/severe LCE during follow-up. DRV users were older and had a lower likelihood of lipid-lowering agent use than DTG users. There was no difference in history of LCE, nor in prevalent or incident LCE between DRV and DTG users. No DILI diagnoses were recorded. Discontinuation following a liver disorder was rare (<1%) across all groups. Conclusion/UNASSIGNED:While PLWH with comorbidities may have been channeled away from EVG and toward DTG and RAL, the incidence of moderate/severe LCE did not differ between DTG and EVG, RAL, and DRV. Plain language summary/UNASSIGNED:cohort, which provides anonymous patient-level clinical data from electronic health records. People living with HIV (PLWH) who were starting a new HIV treatment regimen that included one of four common HIV drugs were included in this study. Liver disorders included drug-induced liver injury (DILI) and moderate or severe liver chemistry elevations. History of a disorder was defined as liver disorders that occurred before starting the new treatment. Prevalent disorders were those that occurred after starting the new treatment in the whole population. Incident disorders were those that occurred after starting the new treatment, but only among PLWH without any history of liver disorders.Out of 16,024 PLWH, 38% initiated dolutegravir (DTG), 43% elvitegravir (EVG), 5% raltegravir (RAL), and 14% darunavir (DRV). EVG users were younger and less likely to have other diseases or use cholesterol lowering drugs compared to DTG users. They were also less likely to have a history of moderate/severe liver chemistry elevations or to have prevalent moderate liver chemistry elevations. RAL users were older and more likely to have other diseases or use cholesterol lowering drugs compared to DTG users. They were also more likely to have prevalent moderate/severe liver chemistry elevations than DTG users. DRV users were older and less likely to use cholesterol lowering agents compared to DTG users. There was no difference in history of liver chemistry elevations, or in prevalent, or incident liver chemistry elevations between DRV and DTG users. There were no DILI diagnoses and discontinuation of treatment following liver disorders was rare across all groups. Overall, the incidence of liver disorders after starting a new HIV treatment regimen did not differ between four common antiretroviral drugs.

BACKGROUND:Researchers must often rely on creatinine measurements to assess kidney function because direct glomerular filtration rates (GFR) and cystatin-c are rarely measured in routine clinical settings. However, HIV treatments often include dolutegravir, raltegravir, rilpivirine or cobicistat, which inhibit the proximal tubular secretion of creatinine without impairing kidney function, thus leading to measurement bias when using creatinine-based estimated GFR (eGFR). We developed eGFR correction factors to account for this potential bias. METHODS:(multivariate Cox proportional hazards models) were estimated with and without eGFR correction. RESULTS:compared to efavirenz. CONCLUSIONS:With increasing use of agents that inhibit tubular creatinine secretion, artificially low eGFR values could lead to erroneous conclusions in studies of HIV treatment and kidney outcomes measured with creatinine-based eGFR equations. Sensitivity analyses assessing the potential magnitude of bias arising from creatinine secretion inhibition should be performed.

Purpose: Given recent evidence that the risk of renal toxicities with TDF may increase with coadministration of a pharmacoenhancer (Hill 2018), we assessed the risk of chronic kidney disease (CKD) associated with TDF and non- TDF containing regimens by D:A:D CKD risk and boosting.
Method(s): ART-naive adults initiating treatment with eGFR>=60 mL/min/ 1.73 m2 (last eGFR within 12 months pre-initiation) were identified in the OPERA cohort. CKD was defined as>=2 consecutive eGFR<60 mL/min/1.73 m2, >90 days apart. The associations between TDF use, baseline D:A:D CKD risk, and incident CKD were assessed with unadjusted incidence rates (IR, Poisson regression) and adjusted survival analyses (pooled logistic regression). Secondary analysis evaluated the contribution of pharmacoenhancers.
Result(s): Of 9,802 PLWH included, 6,222 initiated TDF (76% low-risk D:A:D CKD score, 16% medium-risk, 8% high-risk) and 3,580 did not (79% low-risk, 13% medium-risk, 8% high-risk; Table 1); 40-47% initiated a boosted regimen (Table 2). Overall, 125 incident CKD events occurred over 24,382 person-years of follow-up. Within strata of D:A:D risk score, IRs were similar by TDF exposure, with high baseline CKD risk associated with highest incidence regardless of TDF use (Figure 1). Compared to the low-risk group without TDF, there was no statistical difference in odds of incident CKD in the medium-risk group without TDF (aOR: 2.32, 95% CI: 0.72, 7.52) or the low-risk group with TDF (aOR: 0.55, 95% CI: 0.19, 1.54; Figure 2). Odds of incident CKD did not differ by pharmacoenhancer exposure, with or without TDF.
Conclusion(s): In this large cohort of ART-naive PLWH, incident CKD following ART initiation was relatively infrequent and was strongly associated with baseline CKD risk. TDF-containing regimens did not appear to increase the risk of CKD in those with a low baseline D:A:D CKD risk, the largest group of naive PLWH, and may remain a viable treatment option. (Figure Presented)

BACKGROUND:HLA-B*57:01 screening was added to clinical care guidelines in 2008 to reduce the risk of hypersensitivity reaction from abacavir. The uptake of HLA-B*57:01 screening and incidence of hypersensitivity reaction were assessed in a prospective clinical cohort in the United States to evaluate the effectiveness of this intervention. METHODS:We included all patients initiating an abacavir-containing regimen for the first time in the pre-HLA-B*57:01 screening period (January 1, 1999 to June 14, 2008) or the post-HLA-B*57:01 screening period (June 15, 2008 to January 1, 2016). Yearly incidence of both HLA-B*57:01 screening and physician panel-adjudicated hypersensitivity reactions were calculated and compared. RESULTS:Of the 9619 patients eligible for the study, 33% initiated abacavir in the pre-screening period and 67% in the post-screening period. Incidence of HLA-B*57:01 screening prior to abacavir initiation increased from 43% in 2009 to 84% in 2015. The incidence of definite or probable hypersensitivity reactions decreased from 1.3% in the pre-screening period to 0.8% in 2009 and further to 0.2% in 2015 in the post-screening period. CONCLUSIONS:Frequency of HLA-B*57:01 screening increased steadily since its first inclusion in treatment guidelines in the United States. This increase in screening was accompanied by a decreasing incidence of definite or probable hypersensitivity reactions over the same period. However, a considerable proportion of patients initiating abacavir were not screened, representing a failed opportunity to prevent hypersensitivity reactions. Where HLA-B*57:01 screening is standard of care, patients should be confirmed negative for this allele before starting abacavir treatment.

INTRODUCTION/BACKGROUND:HLA-B*5701 screening identifies patients at increased risk for abacavir (ABC) hypersensitivity reaction (HSR). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and HIV treatment guidelines in 2008. Company meta-analyses of trials pre-HLA-B*5701 screening reported HSR rates of 4% to 8%. We analyzed the effectiveness of HLA-B*5701 screening on reducing HSR rates using clinical trial, observational (OPERA) cohort, and spontaneous reporting data. METHODS:A meta-analysis examined 12 trials in 3063 HLA-B*5701-negative patients receiving an ABC-containing regimen from April 9, 2007 to September 22, 2015. Potential cases were identified using pre-specified MedDRA preferred terms (drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis) and adjudicated against a Company ABC HSR case definition. Investigator-diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC-containing regimen from January 1, 1999 to January 1, 2016 were identified. Patients were observed from regimen start until the earliest-following censoring event: ABC discontinuation, loss to follow-up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR; rates were calculated pre- and post-2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC-containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016. RESULTS:Suspected ABC HSR rates were 1.3% or less in the meta-analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post-2008 versus 1.3% pre-2008 (p<0.0001). Spontaneous reporting rates were low post-2008 (54 to 22 cases per 100,000 patient-years exposure [PYE]) versus pre-2008 (618 to 55 cases per 100,000 PYE). CONCLUSIONS:Clinically suspected ABC HSR rates were 1.3% or less in HLA-B*5701-negative patients. Recognizing their limitations, data from the OPERA cohort and spontaneous reporting indicate that HLA-B*5701 screening has reduced reporting rates of suspected HSR in clinical practice. Where screening for HLA-B*5701 is standard care, patients should be confirmed negative for this allele before starting ABC treatment.

Background: The risk-benefit ratio of ACE-I/ARB therapy after an AKI episode is unclear.
Method(s): We studied 1570 patients recently discharged from hospital and enrolled in a multi-center prospective cohort study (ASSESS-AKI). Follow-up began 3 months after index hospitalization and continued through November 2018. Half of the participants had AKI during the index hospitalization. ACE-I/ARB use and covariates were ascertained 3 months after discharge from the index hospitalization. We used multivariable Cox regression adjusting for demographics, cardiovascular disease, diabetes mellitus, heart failure (HF), blood pressure, urine protein to creatinine ratio, and eGFR to examine the association between ACE-I/ARB use and subsequent death, AKI (>=50% difference between peak and nadir inpatient serum creatinine), renal progression (ESRD or halving of eGFR), and adjudicated HF events.
Result(s): Among study participants who did not have AKI during index hospitalization (N=806), mean age was 65 years, mean eGFR 74 ml/min/1.73m2, and 45% self-reported use of ACE-I/ARB 3 months after hospitalization. Among study participants who did have AKI during index hospitalization (N=764), mean age was 64 years, mean eGFR 65 ml/min/1.73m2, and 50% self-reported use of ACE-I/ARB 3 months after hospitalization. Mean follow-up time was 3.6 years. ACE-I/ARB therapy 3 months after an AKI hospitalization was associated with a lower risk of another hospitalized AKI event and a lower risk of death (Table).
Conclusion(s): Use of ACE-I/ARB in survivors of hospitalized AKI was not associated with increased risk of subsequent AKI but was associated with lower risk of death

Background/UNASSIGNED:Psychiatric outcomes are common among people living with HIV and may be associated with specific antiretroviral use. We evaluated the occurrence of psychiatric outcomes in patients taking dolutegravir (DTG)-containing regimens compared with five other core agents. Methods/UNASSIGNED:Patients in the OPERA database prescribed regimens based on DTG, efavirenz (EFV), raltegravir (RAL), darunavir (DRV), rilpivirine (RPV), or elvitegravir (EVG) for the first time between 1 January 2013 and 31 December 2015 were analyzed. Psychiatric outcomes included diagnoses of anxiety, depression, insomnia, or suicidality during core agent exposure. Multivariable Cox analysis models were used to assess time to psychiatric outcomes between core agents stratified by psychiatric history, with DTG as the referent. Results/UNASSIGNED:EVG and DRV). Conclusions/UNASSIGNED:In a large cohort of HIV+ patients in care, patients with a psychiatric history appeared channeled towards drugs with known favorable psychiatric safety profiles, including DTG. Despite this, DTG exposure was not associated with an increased risk of psychiatric outcomes during follow up in patients with or without a psychiatric history.

INTRODUCTION: Psychiatric symptoms are reported to occur frequently in people living with HIV and may be associated with specific antiretrovirals. We analysed psychiatric symptoms observed with dolutegravir and other frequently prescribed anchor drugs. METHODS: Selected psychiatric symptoms (insomnia, anxiety, depression, and suicidality) occurring in HIV-positive patients during dolutegravir treatment across 5 randomized clinical trials (3 double-blind), in the Observational Pharmaco-Epidemiology Research & Analysis (OPERA(R)) cohort, and among cases spontaneously reported to ViiV Healthcare were analysed. RESULTS: In clinical trials, psychiatric symptoms were reported at low and similar rates in patients receiving dolutegravir or comparators (atazanavir, darunavir, efavirenz, or raltegravir). Insomnia was most commonly reported. The highest rates were observed in SINGLE (dolutegravir 17%, efavirenz 12%), with consistently lower rates in the other trials (dolutegravir: 3%-8% versus comparator: 3%-7%). More efavirenz-treated patients withdrew because of psychiatric symptoms than patients treated with other anchor drugs. In OPERA, history of psychiatric symptoms at baseline was lowest in efavirenz-treated patients compared with patients treated with dolutegravir, raltegravir, or darunavir. Despite baseline differences, prevalence and incidence during treatment were similar across the 4 anchor drugs. Withdrawal rates for psychiatric symptoms were lowest for dolutegravir (0%-0.6%) and highest for raltegravir (0%-2.5%). Spontaneously reported events were similar in nature to clinical trial data. CONCLUSIONS: Analysis of 3 different data sources shows that, similar to other frequently prescribed anchor drugs to treat HIV infection, psychiatric symptoms are also reported in DTG-treated patients. These events are reported with low frequency and rarely necessitate DTG discontinuation.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The standard of care for HIV treatment is a three-drug regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor (PI) or an integrase strand transfer inhibitor. Darunavir boosted with ritonavir (DRV/r) is the only preferred PI in the US Department of Health and Human Services (DHHS) HIV treatment guidelines for antiretroviral-naïve patients, recommended in combination with tenofovir/emtricitabine for antiretroviral-naïve patients. For treatment-experienced and certain antiretroviral-naïve patients, abacavir and lamivudine (ABC/3TC) in combination with DRV/r is considered an effective and tolerable alternative, despite limited research on the effectiveness of this particular combination. This study evaluated virologic outcomes in treatment-experienced patients taking ABC/3TC + DRV/r compared to treatment-experienced patients taking ABC/3TC with any other PI. METHODS:) cohort, a prospective observational cohort reflecting routine medical care. Viral load measurements taken during follow-up were compared between patients taking ABC/3TC + DRV/r and ABC/3TC with a PI other than DRV/r. Logistic regression models were fit to assess the association between regimen exposure and viral load suppression. RESULTS:; p = 0.59] while being treated with the regimen of interest. CONCLUSIONS:Patients receiving ABC/3TC + DRV/r appear to experience similar treatment benefit to patients taking ABC/3TC with other PIs in terms of achieving suppression, as well as absolute reductions in viral load and CD4 lymphocyte gains.