Download 1 Introduction Adherence to Highly Active Antiretroviral Therapy

Name: Shilpa Viswanathan
Thesis Advisor: Dr. Lisa P. Jacobson
The Effect of Concomitant Medications on the Optimal Adherence to Highly Active Antiretroviral
Therapy (HAART)
1 Introduction
Adherence to Highly Active Antiretroviral Therapy (HAART) is an integral component of
treatment success in HIV patients. A high adherence cut-point of 95% was established as
necessary for suppression of HIV RNA (viral load) levels in the early HAART era (1996 to 2005).
However, there have been several barriers to maintaining high adherence levels such as
treatment complexity, side-effects associated with HAART, treatment access issues, lack of
social support, and patient-related behaviors. As a result, physicians have been reluctant to
initiate patients on HAART early-on. In addition, resources have been diverted towards
adherence improvement interventions and comprehensive counseling sessions.
Since 2006, the landscape of HIV treatment has changed, with the introduction of single-pill
regimens (Atripla®, Complera®, Stribild®), and newer formulations with improved
pharmacokinetic profiles (i.e., longer half-lives such as Isentress® and Intelence®).
Consequently, adherence to HAART has become easier than earlier regimens. In parallel,
improved formulations of HAART make HIV RNA suppression possible at lower levels of
adherence, than has historically been the case. The optimal adherence to HAART in the current
HAART era may therefore be lower than the previously established cut-point.
Owing to improved survival and a growing older HIV population, AIDS-related mortality has
declined, and non-AIDS-related morbidity and mortality has increased over the past decade.
While on the one hand, HAART has become easier to use, on the other hand, there has been
an increase in overall treatment complexity in HIV patients as a result of concomitant
medications used to treat non-AIDS comorbidities. Research-to-date has not fully considered
the impact of concomitant medications on optimal HAART adherence.
It is therefore important that clinicians and researchers invested in the safe and effective use of
HAART make recommendations for adherence to HAART in light of the current treatment
scenario. Using information from three long-standing cohort studies - the Multicenter AIDS
Cohort Study (MACS), Veterans Aging Cohort Study (VACS), and the AIDS Linked to
Intravenous Experience (ALIVE), this study aims to quantify the optimum level of adherence to
HAART, and consider the impact of concomitant medications on this new cut-point.
2 Methods
Our study proposes three inter-related aims, each with a distinct approach and study population.
Aim 1: To estimate the minimum adherence level to HAART to achieve HIV RNA suppression
from 2001 through 2011.
Populations: HIV-positive persons in Multicenter AIDS Cohort Study (MACS), AIDS Linked to
Intravenous Experience (ALIVE), and the Veterans Aging Cohort Study (VACS) on
HAART between 2001 and 2011 and seen in the cohort since at least January 1,
2009
Outcome: 1) HAART adherence
2) HIV RNA suppression
Exposure: 1) Time
2) HAART adherence -- self-reported using the MACS and ALIVE, and pharmacy
refill records from the VACS
Statistical Methods: Analysis will be stratified according to the methods used to capture
adherence, and will be done separately for the MACS and ALIVE (combined), and the VACS.
Linear mixed effects models will be used to study the effect of time on adherence using
clustering by patient ID and adjusting for confounders. If time has an effect on the analysis, then
further analysis will be done by time period. ROC curves will be used to define the optimal
adherence cut-point by calendar period. Logistic regression models controlling for confounding
Name: Shilpa Viswanathan
Thesis Advisor: Dr. Lisa P. Jacobson
will be used to examine the association between the optimal adherence cut-point and HIV RNA
suppression, and an interaction term between age and optimal adherence will be included in the
model to test effect modification by age.
Aim 2: To determine the profile of comorbidities and concomitant medications among current
HAART users from 2006 to 2011.
Populations: HIV-positive persons in the MACS and the VACS on HAART
Statistical Methods: The Chronic Condition Indicator (CCI) tool will be used to classify a
condition as chronic or not. The drugs will each be classified according to the Anatomic and
Therapeutic Chemical Classification (ATC) System. Frequency distributions will be used to
describe the dose and mode of administration of the concomitant medication. Bivariate analysis
will be used to describe the concomitant medications and comorbidities by age, CD4 cell count,
and HIV RNA suppression.
Aim 3: To determine the factors related to HAART adherence among current HAART users on
concomitant medications from 2006 to 2011.
Populations: HIV-positive persons in the MACS and VACS on HAART and ≥ 1 concomitant
medication for a chronic condition
Outcome: HAART adherence
Exposure: 1) Number of concomitant medications
2) Physical and mental health summary scores from the SF-12 and SF-36
Statistical Methods: Propensity score adjustment will be used to control for confounding by
indication due to factors that lead to use of greater than the median number of concomitant
medications. Longitudinal regression will be performed, controlling for confounding, and
adjusting for repeated measures per person to (1) Determine the probability of achieving optimal
adherence using logistic regression, with HAART adherence as a dichotomous outcome, (2)
Determine the level of adherence according to exposure categories using linear regression, with
HAART adherence as a continuous outcome.
3 Significance
This project broadly aims to maximize treatment benefits, reduce the barriers to treatment
adherence, and improve the overall treatment outcomes of aging HIV patients in the current
HAART era, with several far-reaching consequences. (1) The optimal adherence cut-point
determined in Specific Aim 1 will enable physicians to prescribe medications to individuals
previously deemed ineligible for the drug because of adherence barriers. Improving access to,
and consistent use of medicines by infected individuals would decrease their risk of transmitting
the virus to others, according to a recent report by the Institute of Medicine (IOM) on HIV
treatment and quality of care. Additionally, recent findings from two separate studies1,2 indicated
cure of patients that were initiated early on HAART. A lower optimal adherence cut-point will
therefore be highly beneficial in reducing the overall disease burden, and in preventing progress
of the disease to AIDS. (2) The successful management of concomitant medications
administered with HAART would decrease the drug-drug interactions, and adverse effects
associated with these medications when used in HIV-infected persons on HAART. A profile of
comorbidities and concomitant medications administered to treat chronic non-AIDS conditions,
will therefore serve as an important resource to physicians. (3) Finally, identifying modifiable
predictors of optimal HAART adherence in the presence of concomitant medications would
ensure that comprehensive adherence improvement interventions can be targeted towards
individuals with specific barriers to achieving the optimal level of adherence to HAART.
2
Name: Shilpa Viswanathan
Thesis Advisor: Dr. Lisa P. Jacobson
4 Budget Allocations
Funding ($1,000) is solicited from the Delta Omega Society for travel to meetings with research
collaborators and to a professional meeting over the next academic year (2013-14).
‒ Due to collaboration with the VACS at Yale University, I will be required to travel to New
Haven, Connecticut at least 3 times over the next year to meet with the VACS group and
present at their research-in-progress meetings. The cost of the train ticket (return) will be
$150*3=$450.
‒ I would like to attend a professional meeting this fall, to which I have submitted an
abstract based on my research – the International Society for Pharmacoepidemiology
(ISPE). Estimated travel & accommodations: $600
The current source of funding for this project comes from funds awarded by the National
Institutes of Health to the MACS.
5
References
1. Sa´ez-Cirio´n A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, et al. (2013) PostTreatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of
Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211.
2. Persaud D et al. Functional HIV Cure after Very Early ART of an Infected Infant. Available at:
http://www.retroconference.org/2013b/Abstracts/47897.htm
Delta Omega Scholarship Application Details:
Name: Shilpa Viswanathan
Program & Year: PhD, Epidemiology (General Epidemiology/Methods track), third year
Thesis Advisor: Dr. Lisa P. Jacobson
Project title: The Effect of Concomitant Medications on the Optimal Adherence to Highly Active
Antiretroviral Therapy (HAART)
Category: Measurement
3