Abstract
Objectives
To describe patterns of antiretroviral medications among people with HIV (PWH) who also have common comorbid conditions in a United States cohort.
Methods
This retrospective cohort study used Optum Research Database claims data from 01/01/2017 through 01/31/2019 to identify adult PWH (≥18 years) based on pharmacy claims for ART during 2018. The index date was defined as the first date of an ART claim. Study inclusion required ≥1 HIV/AIDS diagnosis code during the study period, and continuous health plan enrollment 12 months prior to and at least 30 days after the index date. Descriptive statistics were used to report study results.
Results
The study population consisted of 17,694 PWH; mean (SD) age 52.2 (12.8) years; 62.0% were ≥ 50 years old. About 50.6% of the study sample had ≥2 comorbidities at baseline. The most prevalent comorbid conditions were hypertension (33.2%), hyperlipidemia (29.7%), neuropsychiatric conditions (26.9%), and cardiovascular disease (11.5%). Most (93.5%) of PWH received a nucleotide reverse transcriptase inhibitor (NRTI) backbone regimen, including tenofovir alafenamide (41.6%), tenofovir disoproxil fumarate (28.1%), and abacavir (22.0%). The most commonly used anchor agents, 62.6%, were integrase strand transfer inhibitors (INSTIs): dolutegravir (30.4%), elvitegravir (24.2%), and raltegravir (7.3%). The proportion of PWH using specific ARTs did not vary significantly with the presence and type of comorbidities.
Conclusion
From our analyses, ART prescribing did not appear to vary with the presence of comorbidities and potential medication contraindications. ART regimens may have comparable efficacy profiles; however, selection should be guided by each patient’s comorbidities to prevent potential comedication drug toxicities.
Introduction
In the past two decades, broad access to effective antiretroviral therapy (ARTs) has reduced morbidity and mortality and prolonged life expectancy in people with HIVCitation1–4. In tandem with prolonged life spans, PWH experience accumulated exposure to HIV and ARTs. This results in elevated risk of certain non-infectious, age-related, often chronic, comorbidities including cardiovascular disease (CVD), hypertension, diabetes, chronic kidney disease (CKD) and osteoporosis at an earlier age, and with a greater requirement for comedicationsCitation2,Citation5,Citation6.
In addition, long-term use of ART and sustained HIV-related immune activation may be associated with increased vulnerability to specific inherent toxicities and adverse events, drug-drug interactions and contraindications. These coexisting conditions may include deleterious effects on bone and renal health, neurocognitive and neuropsychiatric dysfunction, weight gain, and intensified cardiovascular risk, especially among older PWHCitation3,Citation7–9.
Current treatment guidelines generally recommend as the initial ART regimen an integrase strand transfer inhibitor (INSTI) anchor agent and two nucleotide reverse transcriptase inhibitors (NRTIs), irrespective of age and CD4 T-cell count. The guidelines also recommend taking comorbidities into consideration when selecting ART regimens for treatment initiation or switchCitation10–13. Risks associated with the management of comorbidities and the potential for inherent adverse events with ARTs may complicate the challenges of providing holistic clinical care for PWHCitation2,Citation8,Citation14.
A study by Marcus et al. that examined 430,000 death records found that a 21-year-old with HIV during the period of 2000–2003 had a life expectancy of 38 years (22 years fewer than a non-affected peer), which increased markedly for the period of 2014–2016 to 56 years (versus 60 years for a non-affected peer)Citation2. As life expectancy increases for PWH, becoming more similar to that of persons without HIV, PWH experience the same aging-related comorbid conditions as persons without HIV. Hence, monitoring choices of ART and co-medications for those with comorbidities is essential for patient management. As a result of combined factors, there is an increasing need for more proactive prevention and timely management of comorbidities among PWH on ARTCitation2,Citation15.
Data regarding ART use and comorbidity management are scarce and usually limited to single types of comorbidities or treatments. These limitations provide the rationale for performing a much larger study. It is important to consider common comorbid conditions in HIV management of aging PWH as the prevalence of many comorbidities increases with ageCitation16. Over the last decade, ARV medications use has changed, with INSTI often considered standard of careCitation10,Citation11. An appropriate choice of ARV medications for treatment of HIV, among PWH with prevalent comorbid conditions is critical in improving quality of lifeCitation2,Citation8.
An appropriate individualized choice of ARV medication is critical in improving overall health and quality of lifeCitation2,Citation8.
The aim of this study was to describe ARV medications prescribing patterns among PWH with commonly observed comorbid conditions in a large sample of PWH in the United States (US).
Methods
Data source and study design
This retrospective cohort study used administrative medical and pharmacy claims, enrollment, and socioeconomic data from the Optum Research Database (ORD). The ORD is one of the largest healthcare claims repositories in the US, which includes data from 1993 to the present with more than 73 million enrollees. As of 2018, the geographically diverse ORD comprised 19% of the US commercially enrolled population, 21% of the Medicare Advantage population, and 22% of the Medicare Advantage Part D population.
All data used for this study were statistically certified as de-identified using techniques compliant with the Health Insurance Portability and Accountability Act, and no identifiable protected health information was extracted. As a result, institutional review board approval and informed consent procedures were not required for this study.
Inclusion and exclusion criteria
Adult (≥18 years) PWH were identified by at least one pharmacy claim for ARV medication during the 2018 calendar year (). The index date was defined as the first date of an ARV medication claim. Continuous health plan enrollment from 12 month prior to (“baseline period”) to at least 30 days after the index date (“post-index period”) was required. At least one HIV/AIDS diagnosis code during the pre-index period starting 01/01/2013 to 30 days after the index date or follow-up periods was required for inclusion. PWH who had pharmacy claims for tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) or tenofovir alafenamide (TAF) plus FTC and no other evidence of another ARV medication during the baseline or post-index periods were likely on pre-exposure prophylaxis (PrEP) and were excluded. In addition, enrollees were excluded if they had diagnosis codes for post-exposure prophylaxis (PEP; ICD-10-CM diagnosis codes Z11.4 and Z20.6) during baseline or post-index periods ().
Study measures
Demographic characteristics identified during the baseline period included age, sex, insurance type, US geographic region, and race/ethnicity. Pharmacy claims for ARV medications (including single-tablet regimens (STR) dated on or within 14 days after the index date) were included for assessment in this study. The anchor agents included the INSTIs dolutegravir (DTG), elvitegravir (EVG), and raltegravir (RAL); non-nucleoside reverse transcriptase inhibitors [NNRTI; including efavirenz (EFV), and rilpivirine (RPV)]; and protease inhibitors [PI; darunavir (DRV) and atazanavir (ATV)], among others. Therapies with small sample sizes, such as the INSTI bictegravir, were not included in the analysis (Appendix ). A total of 67 comorbid conditions were selected from prior literature and identified by diagnosis codes on medical claims where there was at least 1 inpatient admission or at least 2 ambulatory claims on different dates. Comorbidities were identified using International Classification of Diseases Clinical Modifications 9 and 10 (ICD-CM-9/10) diagnosis codes from medical claims dated during the 12-month baseline period, and a Quan-Charlson comorbidity index (CCI)Citation17 was computed, excluding HIV/AIDS. Definitions for each comorbid condition was based on condition categories from the Chronic Conditions Data Warehouse (CCW) published by Centers for Medicare and Medicaid ServicesCitation18, or alternatively on a clinician’s review of relevant diagnosis codes. Conditions included broad categories of cardiovascular diseases, renal diseases, liver diseases, cancer, mental health and pain, lung diseases, autoimmune conditions, endocrine disorders, and gastrointestinal disorders () The number of comorbid conditions from the full listing of 67 observed was summated for a categorical “comorbidity burden” score (0, 1, 2, 3+).
Statistical analysis
In this retrospective study, descriptive statistics were used to report characteristics of PWH focusing on the ART regimens they received, stratified by comorbid conditions. No statistical testing was conducted to determine statistically significant differences across different ARTs. All analyses were conducted using SAS software version 9.0.
Results
Sample selection and attrition
A total of 53,860 PWH were identified with ≥1 pharmacy fill(s) for an ART claim. Upon applying all inclusion and exclusion criteria, 17,694 eligible PWH were retained for analysis ().
Figure 1. Sample selection and Attrition. 1No missing or invalid demographic information. 2HIV diagnosis codes must not be occurring on the same day as an HIV antibody screening test (CPT codes 86689; 86701; 86702; 86703; 87534; 87535; 87536; 87390; and ICD-10 DX Code Z71.7).
Patient characteristics
The study sample (N = 17,694) had a mean (SD) age of 52.2 (12.8) years; 62.0% of PWH were 50 or more years of age (). The majority (82.6%) were male, and 46.9% were Caucasian, and 28.2% were African American, while 13.8% were Hispanic. The largest proportion of patients, 59.1%, were located in the Southern region of the U.S. About two thirds of the PWH had commercial insurance coverage, with the rest enrolled in Medicare Advantage Part D.
Table 1. Baseline demographic characteristics of study sample by ART regimen.
Most common ART medications
During the 2018 calendar year, most PWH (n = 16,549; 93.5%) received an NRTI backbone regimen, including TAF (41.6%), TDF (28.1%), and ABC (22.0%) (). The most commonly used anchor agents were INSTI, by 11,075 (62.6%) PWH: DTG (30.4%), EVG (24.2%), and RAL (7.3%). NNRTI regimens and PI regimens were less frequently used: NNRTI by 5214 (29.5%) PWH, including EFV (13.2%), and RPV (12.2%). PI was used by 3,061 (17.3%) of PWH, most commonly DRV (12.0%) and ATV (3.4%). Other lesser used agents were not included in the analyses.
Overall comorbidity burden
Approximately one-half (50.6%) of the study sample had 2 or more comorbid conditions identified during the baseline period (). The most prevalent comorbid conditions were hypertension (33.2%), hyperlipidemia (29.7%), neuropsychiatric conditions (26.9%) including depression (13.2%) and anxiety (11.0%) type 2 diabetes mellitus (13.1%), cardiovascular disease (11.5%), chronic kidney disease (12.9%), obesity or overweight (12.6%), and gastrointestinal disorders (11.9%).
Figure 2. Comorbidity burden among all patients (n = 17,694). Abbreviations. CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; T2DM, Type 2 diabetes mellitus. CVD includes acute myocardial infarction, cardiac dysrhythmia, ischemic heart disease, heart failure. Neuropsychiatric conditions include depression, anxiety disorders, suicidal ideation, bipolar/manic depression, insomnia and sleep-related disorders, cognitive impairment/poor concentration, opioid use disorders, drug use disorders, and alcohol use disorders.
ART regimens by selected comorbid conditions
The use of specific ART agents did not vary greatly by types of comorbid conditions observed. Out of the total 8948 PWH with >2 comorbid conditions, 32% received DTG, 21.9% received EVG as INSTI anchor agent, and 41.2% and 25.1% received TDF and TAF, respectively, as backbone agent. (). Among these PWH, the following comorbid conditions were observed: diarrhea (44.4%), neuropsychiatric conditions (43.5%), peptic ulcer or esophageal reflux (42.8%), osteoporosis (40.2%), CVD (39.2%), and CKD (36.8%). Similarly, among PWH who received an anchor INSTI, the most frequently observed agent was DTG (30.4%), and there were many types of comorbid conditions: CKD (38.5%), CVD (33.3%), osteoporosis (38.5%), diarrhea (36.4%) and peptic ulcer/esophageal reflux (35.1%), neuropsychiatric conditions (32.5%), obesity or overweight (30.4%), and hyperlipidemia (29.7%). NNRTI use varied between EFV (13.2%) and RPV (12.2%), based on comorbid conditions; for example, people with cardiovascular disease (11.7% and 9.9%), hyperlipidemia (14.0% and 11.6%), hypertension (13.0% and 10.8%), type 2 diabetes (13.7% and 11.0%) and peptic ulcer or esophageal reflux disease (10.5% and 7.4%) were more likely prescribed EFV than RPV, respectively. Conversely, patients with neuropsychiatric conditions were more often prescribed RPV (11.2%) rather than EFV (9.3%). Among PI agents, DRV (12.0%) was prescribed at least 3 to 4 times more often than ATV (3.4%), regardless of the comorbid condition: CKD (17.4% and 4.1%), osteoporosis (13.9% and 2.9%), and gastrointestinal conditions such as diarrhea (17.6% and 3.1%) respectively.
Table 2. ART Agent use by selected comorbid conditions.
Discussion
In this study of a contemporary US cohort of more than 17,000 PWH on ART, one-half of the sample had at least two chronic comorbid conditions; only slight differences were observed in the use of particular ART agents among PWH irrespective of their comorbidity profiles.
Consistent with prior studies in PWH, the most common comorbidities were hypertension, hyperlipidemia, neuropsychiatric conditions, CVD, CKD and obesity/overweightCitation5,Citation19–22. A prior study that conducted a trend analysis on a similar population showed that the prevalence of cardiovascular-related comorbidities increased significantly from 2014 to 2018, as did obesity and overweight, and CKDCitation19. A study by Paudel et al. also reported increases in comorbidity and comedication burdens over the same time frameCitation16. Similar increases were reported over time in trend analyses of comorbidity and comedication by Galant et al. 2003 to 2013Citation20, and Priest et al. 2007 to 2017Citation23. Besides, multiple other studies have shown that PWH treated with ART face greater vulnerability to fractures, osteoporosis, overweight/obesity, renal and metabolic disorders, neuropsychiatric disorders, CVD and liver diseaseCitation3,Citation24–30.
Although the observed pattern of the use of an INSTI anchor agent with two NRTIs is supported by current guideline recommendations based on effectiveness, resistance barrier and activity, guidelines also recommend taking into consideration of the background risk and burden of non-AIDS comorbidity, and other factors such as drug-drug interactions, and polypharmacy to manage multimorbidity in PWHCitation10,Citation12,Citation13. However, the patterns of ART use observed in this study suggest that these considerations are not impacting prescribing practices.
While there is currently no cure for HIV, available evidence suggests that the benefits of viral suppression overwhelmingly offset the risks associated with ART use in practically all instances, especially when tailored to particular comorbidity profilesCitation3,Citation31. Furthermore, although ART regimens have emerged as effective treatment for HIV, each component may be associated with short- and long-term clinically meaningful toxicitiesCitation3. More PWH taking ART for longer periods will inevitably result in greater cumulative toxicity. Older NRTI drugs were linked to mitochondrial toxicity such as myopathy, neuropathy, hepatic failure, and lactic acidosis, which are rarely seen with newer drugs such as emtricitabine, lamivudine, and tenofovir, although tenofovir-based drugs carry new potential short- and long-term toxicities. Both PIs and NRTIs have been implicated in lipodystrophy or changes in fat distribution that could result in loss of fat around the face and increase in trunk fatCitation32.
For the vast majority of patients who received an NRTI backbone agent, the most commonly used medications were TAF and TDF, which was true even in the presence of a range of comorbid conditions including CKD and osteoporosis. Use of TDF is known to be associated with deleterious outcomes for people with CKDCitation33,Citation34. TDF treatment was received by about one-fifth of the patients with osteoporosis. This level of exposure could be a reflection of inappropriate regimen selection. The use of TDF has been shown in prior studies to result in further deterioration in bone mineral density compared to other NRTIs and to be inappropriate for PWH with osteoporisCitation25,Citation35. TAF, which was received by about 40% of the patients with osteoporosis in this study, is typically administered at lower doses because it has greater intracellular penetration. This agent is associated with more satisfactory bone toxicity outcomes, as shown in clinical studiesCitation36,Citation37. The presence of large proportions of patients on TDF and TAF, however, suggest that physicians may not necessarily be making treatment decisions based on the toxicity profile of therapies and the comobidity profile, or increasing age, of PWH in this contemporary population.
PWH in this study with hypertension and diabetes were observed to be on tenofovir regimens, which is concerning as the combination of hypertension, diabetes and tenofovir may exacerbate the risk for CKDCitation38. Tenofovir-sparing regimens may be more appropriate for PWH with CKD and underlying hypertension or diabetesCitation39–41. However, one-eight of PWH with CKD were on a TDF-containing regimens, while another one-third of those PWH were on TAF. Hence, these data are at odds with our understanding of the role of TDF as an important contributor to renal toxcity and its association with worsening CKDCitation33,Citation42. Furthermore, use of TDF is not aligned with the results of studies that evaluated switching from TDF to TAF regimens, which reported improvements in renal markers and a decrease in related adverse events, suggesting it is advisable to avoid TDF agentsCitation43,Citation44.
In this study population, noticeably smaller numbers of patients were prescribed NNRTI treatment regimens. However, NNRTI use slightly differed for EFV and RPV, based on comorbid conditions. PWH with CVD, hyperlipidemia, hypertension, and type 2 diabetes were more likely to be prescribed EFV than RPV, and individuals with neuropsychiatric conditions were prescribed RPV more often than EFV. Until recently, EFV was favored in combination ARTsCitation45. However, it has been shown to induce neuropsychiatric and neurocognitive adverse events, and to have an association with psychoses, nightmares and diminished focus and concentrationCitation45. In our study, approximately one-tenth of the patients with neuropsychiatric conditions received EFV treatment. In addition, patients with peptic ulcer or esophageal reflux disease were prescribed the NNRTI, RPV for which it was contraindicatedCitation46.
Furthermore, small poportion of patients were prescribed PI treatment regimens. Among the PI agents, DRV was prescribed 3- to 4-times more often than ATV, regardless of the comorbid conditions observed. This pattern seems at odds with real-world data that suggest that the most commonly used PI, DRV, was associated with greater risk of cardiovascular eventsCitation30, again reflecting a need to appropriately match regimen selection to patients’ comorbidities. In addition, patients with gastrointestinal conditions such as diarrhea were prescribed the PIs, DRV and ATV, despite being known causes of diarrheaCitation47.
As expected, the ART use pattern for patients who received an anchor INSTI agent was similar across the study population. The most frequently prescribed was DTG, despite the presence of different types of comorbidities. Close to two-thirds (63.2%) of the patients with overweight or obesity were prescribed INSTIs. This mirrors the weight gain seen among older PWH and in the older population overallCitation48–50. INSTIs were first implicated in weight gain in observational studies of patients changing from other treatments to INSTI-based regimensCitation24,Citation51,Citation52. Moreover, results from clinical studies have shown an association between INSTIs and weight gain when used either as initial treatment or as a change of therapyCitation53. In addition, clinical studies have indicated that the use of INSTIs was associated with neuropsychiatric side effects, and higher rates have been reported in newer drugs such as DTG relative to RAL and EVGCitation54,Citation55.
Notably, the high prevalence of comorbidities in this study population would necessitate the use of multiple medications along with ARTs, which leads to polypharmacy and the need for physicians to carefully assess the treatment regimens they are prescribingCitation56,Citation57. The results of this study indicate the potential for drug-disease interactions in the sizeable proportion of PWH who have comorbid conditions. While this study did not evaluate different approaches to managing PWH, the results support the need for physicians to be aware of patients’ comorbidities as well as their potential impact, which could help to underscore the necessity for more informed treatment choices. Furthermore, newer treatment regimens with fewer drugs, that is lower comedication and polypharmacy burdens, could help to assuage the collective complications associated with ART toxicityCitation28.
Limitations
The data in this study were administrative claims data repurposed for research. Using data not designed for research may introduce risks of miscoding, omissions, misinterpretations, and selection bias. This study is primarily descriptive, and no formal statistical tests were conducted to compare treatments and groups. The lack of clinical data in claims precludes analysis of disease severity, adverse events, and drug-drug interactions, among other medical issues. The study sample included a small proportion (less than 6%) of patients who were naïve to treatment in the baseline period, which was unlikely to affect the results. Another limitation surrounds the source data, which include only PWH with Medicare Advantage Part D or commercial health insurance plans. Thus, results may not be generalizable to the uninsured or to PWH insured by Medicaid, Medicare fee-for-service, and the AIDS Drug Assistance Program.
Conclusions
This study described prevalence of various ARV medications used for treatment of HIV among PWH with most common comorbid conditions. Current evidence indicates that successful treatment of HIV with ARTs has resulted in longer lives for PWH. Increasing life spans are typically accompanied by age-related comorbidities. The inherent toxicities of ARV medications may increase risk of development of comorbid conditions or adverse events may exacerbate existing conditions. The results of this study support continuing research toward individualizing treatment of HIV among PWH based on comorbid conditions and inherent ARV toxicities.
Transparency
Declaration of funding
This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc, Rahway, NJ, USA.
Declaration of financial/other relationships
G.P. and B.K.T. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc, Rahway, NJ, USA (Merck). S.G. was working under an internship with Merck & Co., Inc., Rahway, NJ, USA in partnership with The University of Mississippi, University, MS. During the study, M.P., E.K.B., and K.M. were employed with Optum Inc., which was paid to conduct the study under contract with Merck. M.P. is now employed by the Henry M. Jackson Foundation, Bethesda, MD, USA. P.K. reports grant/research support from GSK, Merck, and Gilead; stock ownership with Merck, Pfizer, Johnson & Johnson, GSK, and Gilead; and service as consultant/advisory board member with AMGEN, GSK, Merck, and Gilead. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, contributed to the writing and reviewing of the manuscript, and have given final approval of the version to be published. M.P., G.P., S.G., J.M., and P.K. were involved in the conception and design of the study and data interpretation. E.K.B. and K.M. were involved in the acquisition of data. M.P., G.P., E.K.B., K.M., and P.K. were involved in the data analysis. B.K.T. was involved in the interpretation, writing and critical review of the manuscript.
Human subjects’ protection
The database for this study was statistically certified as de-identified, was accessed in compliance with Health Insurance Portability and Accountability Act (HIPAA) and included no identifiable protected health information. Institutional Review Board approval and informed consent was not required for this study.
Acknowledgements
Writing, editorial support, and formatting assistance were provided by Caroline Jennermann, MS, Gayle L. Allenback and Bernard Tulsi, all employees of Optum. Optum was contracted and compensated for conducting the study by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc, Rahway, NJ, USA. Results in part were presented at the 18th European AIDS Conference, European AIDS Clinical Society, October 27–30, 2021. Online and London, United Kingdom.
Data availability statement
Data used to generate these results cannot be disclosed publicly. Proprietary data obtained from the Optum Research Database may be accessed only with strictest data security and privacy protocols, and oversight with a restrictive license agreement.
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Appendix
Figure A1. Study observation period.
Table A1. Diagnosis codes for HIV/AIDS.
Table A2. Codes for PrEP or PEP encounters.
Table A3. List of ART therapeutic agents and classes.
Table A4. List of CCW comorbid conditions.