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The American Journal of Managed Care April 2016
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Single- Versus Multiple-Tablet HIV Regimens: Adherence and Hospitalization Risk
S. Scott Sutton, PharmD; James W. Hardin, PhD; Thomas J. Bramley, RPh, PhD; Anna O. D’Souza, BPharm, PhD; and Charles L. Bennett, MD, PhD, MPP
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Mircea I. Marcu, PhD; Caprice A. Knapp, PhD; David Brown, PhD; Vanessa L. Madden, BSc; and Hua Wang, MS
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Jennifer King, PhD; Vaishali Patel, PhD; Eric Jamoom, PhD; and Catherine DesRoches, DrPH
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Bruce W. Sherman, MD; Wendy D. Lynch, PhD; and Carol Addy, MD, MMSc
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Scott Hasler, MD; Amanda Kleeman MS; Richard Abrams, MD; Jisu Kim, MD; Manya Gupta, MD; Mary Katherine Krause, MS; and Tricia J. Johnson, PhD
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Marissa Escobar Quinones, PharmD, CDE; Margaret Youngmi Pio, PharmD, BCPS, CDE; Diem Hong Chow, PharmD, CDE; Elizabeth Moss, PharmD, CDE, BCACP; Jeffrey Lynn Hulstein, PharmD, CDE; Steven Micheal Bo
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Peter Cunningham, PhD

Single- Versus Multiple-Tablet HIV Regimens: Adherence and Hospitalization Risk

S. Scott Sutton, PharmD; James W. Hardin, PhD; Thomas J. Bramley, RPh, PhD; Anna O. D’Souza, BPharm, PhD; and Charles L. Bennett, MD, PhD, MPP
Single-tablet regimens are associated with higher adherence rates, decreased hospitalizations, and a higher proportion of patients with undetectable viral load compared with multiple-tablet regimens in patients with HIV/AIDS.
ABSTRACT

Objectives:
To evaluate the impact of antiretroviral therapy as a single-tablet regimen (STR) and multiple-tablet regimen (MTR) on outcomes in human immunodeficiency virus (HIV)/AIDS patients using electronic health records from the Veterans Healthcare Administration (VHA).

Study Design: Retrospective cohort.

Methods: This study evaluated VHA patients to whom HIV medications were dispensed as STRs or MTRs during the study period (January 1, 2006, to July 30, 2012). Patients were followed from the index date (ie, start of regimen) until treatment discontinuation, end of study period, last date of healthcare-related activity, or death. Differences in outcomes of hospitalization, adherence defined as a medication possession ratio of ≥95%, and undetectable viral load were evaluated using a Cox-proportional hazard and logistic model controlling for covariates measured during a 6-month baseline period.

Results: A total of 15,602 patients (6191 STR and 9411 MTR) met all study criteria. The study sample was, on average, aged 52 years with similar CD4 counts (mean ± SD: 432.2 ± 282.8 vs 419.3 ± 280.9; P = .287), but a significantly lower proportion of STR versus MTR patients had an undetectable viral load at baseline (42% vs 46%; P <.001). After controlling for baseline covariates, the STR cohort had twice the odds of being adherent (odds ratio [OR], 1.98; P <.001), 31% had a significantly lower hazard of having a hospitalization (hazard ratio, 0.69; P <.001), and 21% had higher odds of having an undetectable viral load during follow-up (OR, 1.21; P <.001).

Conclusions: STR is associated with higher adherence rates, decreased hospitalizations, and more patients with an undetectable viral load in VHA patients with HIV/AIDS.

Am J Manag Care. 2016;22(4):242-248
Take-Away Points
 
This study:
  • Advances knowledge of managed care decision makers regarding advantages of single-tablet regimens; and
  • Informs formulary decision processes regarding antiretroviral therapy to help improve outcomes in patients with HIV/AIDS.
More than 1 million individuals in the United States are living with human immunodeficiency virus (HIV) infection, representing an increase over the past 10 years, with an average incidence of approximately 50,000 new diagnoses per year.1,2 For patients living with HIV, antiretroviral therapy (ART) has transformed the disease and directly resulted in reduced morbidity and mortality from HIV-associated illness. Therefore, current HHS guidelines recommend the initiation of ART in HIV patients to reduce the risk of disease progression and for the prevention of transmission of HIV.3

Despite the importance of ART in managing HIV, barriers to adherence still exist; adherence rates are less than optimal and range from 60% to 80%.4-7 The clinical consequences of poor adherence to ART are well documented and include incomplete viral suppression, disease progression, and death,3,4,8-11 whereas HIV viral suppression, reduced rates of resistance, increased survival, and improved quality of life are associated with ART adherence.3 Drug resistance, with a prevalence of 6% to 16%, is an important consequence of nonadherence.3

HIV guidelines recommend preferred ARTs that include single-tablet regimens (STRs) and multiple-tablet regimens (MTRs). Among other factors—including, but not limited to, presence of adverse events, depression, alcohol and drug use, work schedules, changes in daily routines, and decrease in cognitive function—the high daily pill burden of MTR ART regimens is associated with a decrease in adherence to ART,12-14 and is a strong predictor of discontinuation of combination ART.15 The number of pills in a regimen and number of daily doses correlate with adherence rates.12-17 When MTR options are available, discordant adherence to individual components of an ART regimen can occur.13,15,16

Current treatment guidelines recommend 4 or fewer pills per day with once- or twice-daily dosing.3,18,19 Studies of STRs have shown significant improvements in patient adherence and virologic outcomes20-22; therefore, the role of regimen factors, such as pill burden, is critical to improving adherence. The purpose of the current study is to evaluate the impact of STRs versus MTRs on adherence to highly active antiretroviral therapy (HAART) and the associated risk of hospitalization in patients with HIV receiving care within the Department of Veterans Affairs (VA) Veterans Health Administration (VHA) system. In addition, the impact of STRs and MTRs on viral load was explored.

METHODS
This retrospective cohort study was conducted using data from the VHA electronic health record (EHR) system. The VHA EHR includes clinical and utilization information from 14 million unique individuals receiving care from 140 VA medical centers and 600 outpatient clinics across the United States. The VHA facilities provide a broad spectrum of medical, surgical, and rehabilitative care. National VHA EHR data were searched to obtain individual-level information on demographics, administrative claims, vital signs, mortality, laboratory results, and pharmacy dispensation. (The completeness, utility, accuracy, validity, and access methods of the available data are described on the VA website.)

Study Design and Sample Selection

The date of the first HAART regimen identified during the enrollment period (July 1, 2006, to September 30, 2011) was designated as the index date. Patients were required to remain on their HAART regimen for a minimum of 60 days after the index date and to have continuous enrollment in the VHA for at least 6 months before and 60 days after the index date (eAppendix Figure 1 [eAppendices available at www.ajmc.com]). The follow-up period varied for each patient; however, a 60-day minimum follow-up period was required to ensure that the treatment was being received and that outcomes could be attributed to treatment.

Patients who had a dispensation for any of the drugs of interest were identified as the initial study population. Drugs of interest encompassed 5 classes of drugs included in a complete HAART regimen: a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI), a nonnucleoside/nucleotide reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), a chemokine receptor 5 (CCR5) antagonist, and an integrase inhibitor. From this study population, patients were included if they had a diagnosis or past medical history of HIV/AIDS during the study period and receipt of a complete HAART regimen during the enrollment period. A complete HAART regimen was defined as a regimen containing 2 NRTIs plus a third agent (ie, another NRTI, an NNRTI, a PI, a CCR5 antagonist, or an integrase inhibitor). Additionally, patients had to have at least 1 clinical encounter, 1 pharmacy encounter, and 1 laboratory encounter at a VHA facility within 6 months after the index date.

After initial identification, patients were categorized based on the daily pill count of their complete HAART regimen into either an STR or MTR cohort. Patients were assigned to the STR cohort if they received a complete HAART regimen consisting of a single tablet at any point during the enrollment period, regardless of prior or subsequent use of other regimens. Patients were assigned to the MTR cohort if they received a complete HAART regimen consisting of 2 or more tablets per day at any point during the enrollment period and if they did not receive a regimen consisting of a single tablet per day at any point during the enrollment period.

Study Outcomes

The follow-up periods were variable for each patient; patients were followed from the index date (ie, start of HAART regimen) until the earliest of treatment discontinuation, end of study period, last date of healthcare-related activity noted in the database, or death. Outcomes were assessed for a minimum of 60 days and included adherence—defined as having a medication possession ratio (MPR) ≥95%—and clinical outcomes, assessed by hospitalizations and viral load. Adherence was also alternately defined using the common threshold of ≥80%.

Briefly, MPR is a composite measure that evaluates both medication skipping and discontinuation. MPR was calculated over the duration of the patient’s HAART regimen using the number of days for all HAART regimen components (from pharmacy claims data) divided by the number of days between the first and last fill date of HAART, multiplied by 100. The hazard and number of hospitalizations during the follow-up period were both evaluated. Any hospitalization was considered, regardless of diagnosis.

Data on viral load during follow-up was obtained for each patient, where available, at the visit closest to the date of end of treatment. Undetectable viral load was defined as having a viral load value <50 copies/mL or a result report interpretation of being negative/undetectable in the blood depending on the assay used. Additionally, mean viral load values were also reported.

Statistical Analyses

A descriptive analysis of the final sample was performed using standard summary statistics, such as means and proportions. Baseline characteristics captured during the pre-index period included the following: age, gender, race, geographic region, index year, pre-index medications, Charlson comorbidity index (CCI) score,23 presence of mental health disorders or drug/alcohol abuse, and CD4 count. Inter-cohort differences were quantified using t tests for continuous variables and χ2 tests for categorical variables.

Cohort differences in mean MPR values and the proportion of patients defined as being adherent based on MPR threshold values (≥80% and ≥95%) were evaluated. Adjusted differences in mean MPR values between cohorts were assessed using multivariate ordinary least squares regression. Cox proportional survival analysis models were used to evaluate differences in the hazards of experiencing hospitalization and having a detectable viral load during follow-up. Additionally, Poisson models were used to evaluate differences in the number of hospitalizations, and they incorporated the differing lengths of follow-up of the patients.

All multivariate statistical analyses were adjusted for potential confounders (ie, age, race, geographic region, CCI score, mental health disorders, drug/alcohol abuse disorders, index year, treatment-naïve status, and number of pills per day). For patients with viral load information in the pre-index period, pre-index viral load was included as an additional covariate. Pre-index viral load was obtained from the EHR at the visit closest to the index date. All statistical tests that were performed tested a 2-sided hypothesis of no difference between treatment groups at a significance level of .05.

RESULTS
A total of 24,852 patients with HIV/AIDS were identified in the VHA EHR data set. Of these, 15,602 patients met all the study criteria and comprised the study population (eAppendix Figure 2), 9411 patients (60.3%) received an MTR of HAART, and 6191 (39.7%) received an STR. Patients were excluded mainly due to the following: lack of a HAART regimen for a minimum of 60 days after the index date (22.9%), noncontinuous eligibility during the pre-index period (17.2%), and noncontinuous eligibility during the first 60 days of the follow-up period (8%).

As expected, the majority of patients were male (97.4%) with a mean age of 52 years (Table 1). Overall, the comorbidity burden among the study sample was moderate; patients receiving an MTR had a slightly higher comorbidity burden, as shown by higher CCI scores (1.7 vs 1.5; P <.001) and prevalence of mental health disorders (67% vs 64%; P <.001). Two-thirds of the sample had diagnoses for mental health disorders, with about 40% having drug and substance abuse disorders; no difference was noted in the cohorts in the prevalence of drug and substance abuse disorders. A significantly higher proportion of STR patients were treatment-naïve compared with MTR patients (28% vs 13%; P <.001). All STR and MTR patients received an NRTI; however, the majority of STR patients received an NNRTI (92.8%) and the majority of MTR patients received a PI (69.3%). At study entry, a significantly lower proportion of STR patients had an undetectable viral load compared with MTR patients (42% vs 46%; P <.001); however, the cohorts were similar in terms of CD4-positive counts at baseline.

Adherence Outcomes

 
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