The Incidence and Severity of Drug Interactions Before and After Switching Antiretroviral Therapy to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Treatment Experienced Patients

Study Overview
=================
Brief Summary
-----------------
This study will assess changes in the incidence and severity of drug interactions before and after switching antiretroviral therapy to bictegravir/emtricitabine/tenofovir alafenamide-based regimens in treatment experienced patients living with HIV infection.

Detailed Description
-----------------
Simple, safe and effective antiretroviral therapy (ART) can provide optimal treatment outcomes for people living with HIV infection (PLWH) [1]. Increasingly complex and poorly tolerated regimens, on the other hand often limit ART adherence, while drug-drug interactions (DDIs) and safety concerns with individual ART agents can limit treatment selection [2-4]. Fortunately, recent advances in ART have included the emergence of several highly effective, safe and well tolerated regimens with limited DDIs. In clinical trials, integrase strand transfer inhibitors (INSTIs) such as raltegravir, elvitegravir, dolutegravir and bictegravir are consistently as effective or more effective than comparator agents and often superior in terms of tolerability [5-10]. Due to their efficacy, safety, and tolerability, INSTI-based regimens are now routinely used in treatment naïve patients and emerging data suggests that several may be used to simplify therapy for selected patients with treatment experience [11, 12]. Among the INSTIs, bictegravir is the newest agent in the class [13]. Similar to dolutegravir and raltegravir and in contrast to elvitegravir, it has few significant drug-drug interactions. Unlike dolutegravir and raltegravir, bictegravir is available as part of a single-tablet, once-daily regimen that includes tenofovir alafenamide and emtricitabine (BIC/TAF/FTC). Raltegravir is not available within a single tablet regimen, while dolutegravir is available as part of a single-tablet regimen, but it includes abacavir, which has been linked to an increased cardiovascular disease risk. As a result, BIC/TAF/FTC is currently among the most effective, safe, well-tolerated treatment options with limited drug-drug interactions. With several new treatment options available, particularly in the INSTI class, current guidelines advocate switching ART when possible in virologically suppressed, ART experienced patients [1]. Switching ART can simplify treatment, improve tolerability, eliminate toxicity, and mitigate drug-drug interactions. When switching ART for any reason, it is critical to review a patient's full HIV treatment history, including virologic responses, past ART-associated toxicities, and cumulative resistance before selecting a new regimen [1]. Drug-drug interaction assessments with a patient's concomitant medications should also be performed prior to switching ART. More than 70% of the HIV population will be above the age of 50 by the year 2020 and many are receiving 5 or more medications for common chronic conditions in addition to being ART experienced [14, 15]. Cardiovascular disease, hepatic and renal disease, osteoporosis, insulin resistance, metabolic disorders, and cancers are among the conditions that can occur more commonly in PLWH and at times earlier in life in comparison to their HIV negative counterparts [16]. Drug-drug interactions between medications needed to treat or prevent these comorbid conditions can often interact with ART. Switching ART, in many circumstances can reduce the number drug interactions with medications for comorbid conditions. Conversely, switching can also lead to new interactions requiring intervention to avoid toxicities or prevent ineffective treatment. Multiple studies have confirmed that switching HIV treatment can improve patient adherence and quality of life [17]. Several studies have also confirmed that clinically significant drug-drug interactions are common in patients living with HIV, but none have assessed changes in the incidence and severity of drug-drug interactions in the setting of ART switches [18-20]. The primary objective of this study is to assess changes in the incidence and severity of drug interactions before and after switching ART to BIC/TAF/FTC -based regimens in treatment experienced patients. Null Hypothesis: There is no difference in the incidence and severity of drug-drug interactions between ART and concomitant medications before and after switching to a BIC/TAF/FTC-based ART regimen in treatment experienced patients. Alternative Hypothesis: The incidence and severity of drug-drug interactions between ART and concomitant medications is reduced after switching to a BIC/TAF/FTC-based ART regimen in treatment experienced patients. Data Collection Subjects from the Jefferson Infectious Diseases Associates outpatient HIV Clinic will be evaluated for study inclusion. Co-investigators at six partner institutions will also evaluate patients at their HIV clinics for study inclusion. The following information will be collected for patients meeting the study criteria: age, gender, race, duration of HIV infection, duration of ART treatment, number of previous ART regimens, CD4+ cell count and HIV RNA directly prior to switching to a BIC/TAF/FTC-based ART regimen, and the reason for switching ART to a BIC/TAF/FTC-based regimen. Additionally, all concomitant medication names at the time of the ART switch will be collected. Scoring System To assess the combined incidence and severity of drug interactions with concomitant medications (CM) prior to and following each patient's ART switch, a DDI incidence and severity score was developed. The score is based upon results obtained when entering medications into the University of Liverpool's HIV Drug Interaction Checker (ULHDIC) database [21]. Each ART-CM pair is given one of the following scores: do not co-administer is assigned a score of 2, potential interaction a score of 1, and potential weak interaction or no interaction a score of 0. For those interactions that have no clear data, or for those medications that are not listed in the drug database, the Department of Health and Human Services HIV treatment guidelines will be consulted along with the FDA product labeling. Score Validation A separate analysis (data not provided here) was completed by study investigators to validate the use of the ULDIC severity ranking. The medication profiles of a random, representative sample of the study's population were selected for analysis. Drug interaction scores using the aforementioned ULHDIC were compared with drug interaction scores determined manually using the Department of Health and Human Services HIV treatment guidelines and FDA product labeling. No statistical difference in drug interaction scores between methods was observed. Primary Endpoint The primary endpoint of the study will be to measure the change in mean total drug interaction scores pre and post ART switch to a BIC/TAF/FTC-based ART regimen. The total drug interaction scores for each patient pre- and post-switch will be calculated. The average pre-switch and post-switch scores will then be determined and analyzed for statistical differences using a two-sided paired t-test (normal distribution) with an alpha level of 0.05 or a Wilcoxon Ranked Sum test (non-normal distribution). Secondary Endpoints The secondary endpoint of the study will be to identify predictors of achieving drug interaction score reductions after switching to a BIC/TAF/FTC-based ART regimen. Predictors for achieving drug interaction score reductions will be examined using a multivariable linear regression model. Initial models will include all a priori determined variables and all variables will be examined for multi-collinearity. Models will be fit using a backwards selection procedure. Candidate predictors will be eliminated individually by comparing the log likelihood ratio test for each model step and using the 5% significance level.

Official Title
-----------------
The Incidence and Severity of Drug Interactions Before and After Switching Antiretroviral Therapy to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Treatment Experienced Patients

Conditions
-----------------
HIV/AIDS

Intervention / Treatment
-----------------
* Drug: bictegravir/emtricitabine/tenofovir alafenamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV diagnosis 18 years of age or older Receiving ART for at least 3 months ART is switched to bictegravir/emtricitabine/tenofovir alafenamide between 2/7/2018 and 3/30/2019 Patient is receiving at least one chronic or as needed non-ART medication at the time of the switch Exclusion Criteria: -

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: bictegravir/emtricitabine/tenofovir alafenamide|Treatment experienced patients with HIV infection that switched to a bictegravir/emtricitabine/tenofovir alafenamide-based ART regimen|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in drug interactions after switching to bictegravir/emtricitabine/tenofovir alafenamide | The primary endpoint is to measure the change in mean total drug interaction scores pre and post ART switch to a bictegravir/emtricitabine/tenofovir alafenamide-based regimen. The total drug interaction scores for each patient pre- and post-switch will be calculated using a drug interaction score developed for this study. The score is obtained when entering a patient's ART and concomitant medications (CM) into the University of Liverpool's HIV Drug Interaction Checker database [21]. Each ART-CM pair is given one of the following scores: do not co-administer is a score of 2, potential interaction a score of 1, and potential weak interaction or no interaction a score of 0. When no interactions are observed between a patient's ART and CMs, the total score will be 0. Higher scores occur when interactions are present. A decrease in score indicates that switching to bictegravir/emtricitabine/tenofovir alafenamide decreased the number and severity of interactions present. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictors of achieving drug interaction score reductions after switching to bictegravir/emtricitabine/tenofovir alafenamide | The secondary endpoint of the study is to identify predictors of drug interaction score reductions after switching to a bictegravir/emtricitabine/tenofovir alafenamide. Predictors will be examined using multivariable linear regression. Initial models will include all a priori variables which will be examined for multi-collinearity. Models will be fit using a backwards selection procedure. Candidate predictors will be eliminated individually by comparing the log likelihood ratio test for each model step and using the 5% significance level. | 1 year |