Abstract
Polypharmacy poses risks associated with drug-drug interactions, increased adverse effects, pill burden, poor compliance and unfavorable treatment outcomes. Whether polypharmacy affects treatment outcomes among people living with HIV (PLHIV) is largely unknown. A prospective study was conducted among PLHIV followed-up at a tertiary-care clinic of an academic medical center during January 2012 to December 2017. The clinic provided comprehensive HIV care with multidisciplinary team approach focusing on treatment adherence. Polypharmacy was defined as concurrent use of 5 or more non-antiretroviral (ARV) drugs for at least one year. Of the 248 PLHIV included, 23 (9%) received polypharmacy. PLHIV with polypharmacy were older (median age 45 vs. 36 years), were more likely to have underlying diseases (65% vs. 18%) and had lower median initial CD4 counts (40 vs. 214 cells/mm3). The rates of virologic suppression at 12 months after ARV therapy were 96% and 92% in polypharmacy and non-polypharmacy groups, respectively (P = 0.70), while the median CD4 cell count increase was higher among the non-polypharmacy group at 12 months (207 vs. 403 cells/mm3; P < 0.001). There were no differences in rates of adverse effects and experienced drug-drug interactions. Hospitalization due to HIV-related diseases within 12 months after ARV initiation [adjusted odds ratio (aOR) 11.63, P = 0.004] and lower 3-item score for ARV adherence (aOR 0.49, P = 0.01) were independently associated with failure of virologic suppression at 12 months. These findings suggest that polypharmacy did not affect the virological outcomes among our PLHIV. Patients with the characteristics associated with virological failure should be closely monitored.
Introduction
Effective antiretroviral (ARV) therapy has increased life expectancy of people living with human immunodeficiency virus (PLHIV) and led to a global aging HIV population. The longevity of PLHIV comes with comorbidities requiring further treatment. Polypharmacy is one of the treatment challenges and generally defined as the use of 5 or more concomitant medications. 1 The prevalence of polypharmacy in PLHIV ranges from 24% to 42% depending on the cohorts’ age and characteristics2–6 and is related to drugs for treatment of opportunistic infections, co-infections and underlying medical and psychiatric illnesses. In one setting, the prevalence of polypharmacy was reported to be higher in PLHIV than those without HIV infection. 5
Previous studies among PLHIV demonstrated the association between polypharmacy and hospitalization, 2 mortality, 2 risk of drug-drug interactions 3 and interrupted ARV therapy. 6 However, none of these studies evaluated the impact of polypharmacy specifically on HIV virological and immunological outcomes while PLHIV were on ARV drugs and compared such outcomes between PLHIV receiving or not receiving polypharmacy treatment. Only one study reported that PLHIV with polypharmacy had 46% poorer virologic control than those without polypharmacy. 4 Nonetheless, this study is based on surveys and all data and outcomes are self-reported. This study aims to evaluate the impact of polypharmacy on HIV treatment outcomes, drug-drug interactions, adverse events and care retention among PLHIV with and without polypharmacy who were prospectively followed-up after the ARV therapy initiation.
Methods
Study design and setting
A study was conducted among a cohort of adult PLHIV (aged ≥18 years) who were prospectively followed-up during the period from 1 January 2012 to 31 December 2017 at the HIV clinic of Thammasat University Hospital, a tertiary-care academic center in central Thailand. The clinic provided comprehensive multidisciplinary HIV care, consisting of infectious diseases physicians, nurses, nurse assistants, pharmacists, social workers and volunteers living with HIV, actively engaged the patients in care, educated and counseled the patients about treatment adherence, called patients who had missed appointments to rearrange for appointments and medication refills. The study was conducted in accordance with the amended Declaration of Helsinki and approved by Faculty of Medicine, Thammasat University Ethics Committee.
Study protocol, definitions and outcome measurement
All eligible PLHIV provided informed consent to participate in the study. Polypharmacy was defined as receipt of ≥ 5 non-ARV drugs continuously for at least a 12-month period since the ARV therapy initiation. Exclusion criteria were receipt of polypharmacy treatment shorter than 12 months after ARV therapy initiation (for PLHIV in polypharmacy group), lost to follow-up and being transferred to receive care at other facilities before the study outcomes could be assessed. Data collected included demographic, clinical and HIV-related characteristics. ARV adherence was measured by scheduled and unannounced pill counts at every visit and the 3-item Center for Adherence Support Evaluation (CASE). 7 The 3-item CASE score was calculated based on punctuality of ARV use, missing doses and time since missing last ARV dose. The primary outcome was HIV virologic suppression, defined as <20 copies/ml at 12 months after ARV therapy initiation while secondary outcomes were change in CD4 count, ARV adherence, adverse reactions and drug interactions, rate of follow-up and hospitalization during the first 12 months of ARV therapy. These outcomes were compared between PLHIV in polypharmacy and non-polypharmacy groups.
Statistical analysis
Given there have not been studies on virological outcome comparing between PLHIV receiving polypharmacy and non-polypharmacy, we estimated the rate of virologic suppression among PLHIV with non-polypharmacy of 95% based on our annual HIV outcome review in 2011 and the rate among patients with polypharmacy of 70%. According to our clinic database, the ratio of PLHIV with polypharmacy to those with non-polypharmacy was approximately 1 to 10. To detect this difference in rates of virologic suppression with the level of significance of 0.05 and power of 0.8, the sample size required was 21 for polypharmacy and 210 for non-polypharmacy groups. Data analysis was performed using SPSS version 23 (Chicago, IL, USA). Pearson’s χ2 or Fisher’s exact test was used to compare categorical data, as appropriate. Continuous variables were compared using the Mann-Whitney U-test. Adjusted odds ratio (aOR) and 95% confidence interval (CI) were calculated in multivariable logistic regression analysis to determine factors associated with failure of virologic suppression at 12 months after ARV therapy initiation.
Results
Baseline characteristics of the study patients
There were 374 eligible PLHIV during the study period and 126 were excluded due to receipt of polypharmacy treatment shorter than 12 months after ARV therapy initiation (N = 85), lost to follow-up (N = 15) and being transferred to receive care at other healthcare facilities (N = 26) before the study outcomes could be assessed. Baseline characteristics of PLHIV who were excluded and were included in the final cohort were comparable. Demographic and clinical characteristics of the 248 PLHIV in the final cohort are shown in Table 1. The median age was 37 years. Most were male (71%) and contracted HIV via heterosexual sexual contact (58%). The median initial CD4 cell count was 188 cells/mm3. Of these 248 PLHIV, 23 (9%) received polypharmacy treatment and 225 (91%) received non-polypharmacy treatment for at least 12 months after ARV therapy initiation. PLHIV in the polypharmacy group were older (median age 45 vs. 36 years; P = 0.014), more-likely to have other comorbidities (65% vs. 18%; P < 0.001), had lower median initial CD4 cell count (40 vs. 214 cells/µL; P < 0.001) and were more-likely to have opportunistic infections (OIs) at baseline (61% vs. 18%; P < 0.001) than those in the non-polypharmacy group. Other baseline characteristics were not significantly different (Table 1).
Baseline characteristics of the 248 people living with HIV in this study.
Data are in number (%) unless otherwise indicated. HIV = human immunodeficiency virus; IQR = interquartile range.
aComparing between polypharmacy and non-polypharmacy group.
bDuration from the time the participants were aware of their HIV-infected status to the time of study enrollment.
Treatment characteristics
Treatment characteristics of the study PLHIV are shown in Table 2. The most common ARV regimens used were non-nucleoside reverse transcriptase inhibitor-based regimens (96%) while the three most commonly used non-ARV drugs were drugs for opportunistic infection treatment, cardiovascular diseases and hypertension. Most PLHIV were 100% adherent to ARV drugs (57%) and present for follow-up as appointed (88%). Compared to PLHIV in the non-polypharmacy group, those in polypharmacy group received significantly more types and higher number of pills of non-ARV drugs, while the rates of ARV adherence and follow-up and the 3-item score were not significantly different between the two groups.
Treatment characteristics and outcomes of the study population.
Data are in number (%) unless otherwise indicated. HIV = human immunodeficiency virus; CNS = central nervous system; CVS= cardiovascular system; DM = diabetes mellitus; IQR = interquartile range; NNRTI = non-nucleoside reverse transcriptase inhibitor; OI = opportunistic infection; PI = protease inhibitor.
aComparing between polypharmacy and non-polypharmacy groups.
bBased on the 3-item Center for Adherence Support Evaluation (CASE) adherence index7 The total score is 16.
cEach participant could have more than one adverse reactions.
Outcomes
After 12 months of ARV therapy, the rates of virologic suppression were comparable between polypharmacy and non-polypharmacy groups (96% vs. 92%) but CD4 cell count had increased significantly more in the non-polypharmacy group (+403 vs. +207 cells/mm3; P < 0.001) (Table 2). ARV and non-ARV drug-drug interactions were reported in 2 PLHIV in the non-polypharmacy group; one had protease inhibitor (PI) and ergotamine interaction resulting in critical limb ischemia and the other one had PI and antipsychotic drug interaction resulting in QT prolongation. Of the 248 PLHIV, 14% had ARV drug-related adverse events. The three most common adverse events were skin rashes (7%), gastrointestinal side effects (4%) and neuropsychiatric side effects (4%). The occurrence rates of drug-drug interactions, drug-related adverse events, and new onset of opportunistic infection were not significantly different between the polypharmacy and non-polypharmacy groups except for the higher rate of hospitalization due to non-HIV-related diseases in the polypharmacy group (9% vs. 1%; P = 0.044) (Table 2).
During the 12-month follow-up period, none of the patients developed immune reconstitution inflammatory syndrome or died. At 12 months after ARV therapy initiation, 20 PLHIV (8%) did not achieve virologic suppression. Compared to PLHIV with virologic suppression, those without virologic suppression had lower median 3-item score for ARV adherence (13 vs. 16; P < 0.001), were more-likely to be hospitalized due to HIV-related diseases (15% vs. 2%; P = 0.013), not 100% adherent to ARV therapy (70% vs. 41%; P = 0.017) and experienced more major drug allergy (10% vs. 0.4%; P = 0.018). HIV-related diseases requiring hospitalization were tuberculosis (N = 3), pneumocystis pneumonia (N = 2), cryptococcosis (N = 1) and diffuse large B-cell lymphoma (N = 1). By multivariable logistic regression analysis (Table 3), independent factors associated with failure of virologic suppression were hospitalization due to HIV-related diseases within 12 months after ARV initiation (aOR 11.63, P = 0.004) and lower 3-item score for ARV adherence (aOR 0.49, P = 0.01). Other demographic, clinical, HIV, treatment, adverse events and outcome characteristics as well as presence of OIs at the first visit were not significantly different between PLHIV with and without virologic suppression.
Univariable and multivariable logistic regression analyses for significant factors associated with failure of virologic suppression at 12 months after antiretroviral therapy initiation.
aBased on the 3-item Center for Adherence Support Evaluation (CASE) adherence index. 7
Discussion
Our study demonstrated that virological outcome at 12 months after ARV initiation was not significantly different between those receiving polypharmacy and non-polypharmacy treatment. The result was confirmed by the multivariable analysis after adjusting for the potential confounding factors. Our result was different from the results reported from another study which showed inferior virological outcomes among the polypharmacy group. 4 However, that study did not describe characteristics of HIV care, patient adherence, care retention and management strategies and was conducted in survey design based on patients’ self-reported information. The similar virological outcome between the two groups in our study could be explained by the similar rates of ARV adherence, retention in care, adverse events and drug-drug interactions. These comparable intermediate outcomes likely resulted from our clinic’s comprehensive care focusing on ARV adherence and engaging patients in care and education on ARV therapy through a multidisciplinary team approach. Although the immunological response was inferior in the polypharmacy group, this group was older and had lower baseline CD4 cell count, both known factors for reduced CD4 rise; 8 both polypharmacy and non-polypharmacy groups had median CD4 cell count increase >200 cells/µL within 12 months of ARV therapy. It should be noted that higher proportion of the patients in the polypharmacy group had comorbidities compared to those in the non-polypharmacy group. This is likely due to the older age of the polypharmacy group.
We identified the lower 3-item score and hospitalization due to HIV-related diseases as independent risk factors associated with failure of virologic suppression at 12 months after ARV therapy. The low score represented poorer adherence to ARV drugs 7 and thus increased risks for virologic failure after ARV therapy. Most of the HIV-related diseases requiring hospitalization in this study were opportunistic infections and HIV-related malignancies. These diseases could impact HIV virological outcome by direct immune suppression effect and/or change in pharmacokinetics/pharmacodynamics of ARV drugs during the acute illnesses. These results suggest the need for close monitoring of virologic failure in patients with poor adherence to ARV drugs and hospitalized due to HIV-related diseases within 12 months after ARV initiation.
The strength of this study is that it is the first to evaluate the impact of polypharmacy on specific ARV treatment outcomes in an HIV cohort which was followed prospectively after ARV therapy initiation. This enabled us to assess detailed information on ARV characteristics, adherence, adverse events, drug-drug interactions, hospitalization and other clinical outcomes that might confound the effect of polypharmacy. The prerequisite criteria to include only patients continuously on ≥ 5 non-ARV drugs concurrently with ARV therapy for the whole 12-month period ensures the accurate assessment of the polypharmacy effect. The study limitations included the non-randomized design resulting in differences in some characteristics between the two groups. Nonetheless, the multivariable logistic regression analysis did not reveal the association between polypharmacy and failure of virologic suppression. Given that polypharmacy in our cohort was mostly due to drugs for OIs rather than drugs for chronic medical illnesses and our patients were younger than those reported in other cohorts,2–4,6 the generalizability of these study results may be limited to other settings with comparable patient characteristics.
In conclusion, the study findings suggest no effect of polypharmacy on virological outcome at 12 months after ARV therapy among PLHIV in the setting where multidisciplinary HIV care, education and counseling on adherence and drug use were provided. However, PLHIV with poorer ARV adherence evaluated during each visit or those hospitalized due to HIV-related diseases should be closely monitored for virologic failure. Further larger prospective studies are needed to confirm the study findings and their validity in other settings.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
