Abstract
Aims
We quantified concomitant medicine use and occurrence of potential drug–drug interactions in people living with HIV in Australia who are treated with antiretroviral therapy (ART).
Methods
In this cohort study using dispensing claims of a 10% random sample of Australians, we identified 2230 people dispensed ART between January 2018 and December 2019 (mean age 49.0 years, standard deviation 12.0 years, 88% male). We examined concomitant medicine use by identifying nontopical medicines dispensed within 90‐days of any antiretroviral medicine dispensing during a 12‐month follow‐up period. For every antiretroviral and nonantiretroviral pair, we identified and classified possible drug–drug interactions using the University of Liverpool HIV drug interactions database.
Results
A total of 1728 (78%) people were dispensed at least 1 and 633 (28%) 5 or more unique medicines in addition to ART in a 12‐month period; systemic anti‐infectives and medicines acting on the nervous system were the most common (68% and 56%, respectively). Among comedicated people, 1637 (95%) had at least 1 medicine combination classified as weak interactions, 558 (32%) interactions requiring close monitoring/dose adjustment and 94 (5%) that should not be coadministered. Contraindication or interactions requiring close monitoring/dose adjustment were more common among people receiving protease inhibitors (50–73% across different antiretrovirals), non‐nucleoside reverse transcriptase inhibitors (35–64%), people using single‐tablet combinations containing elvitegravir (30–46%) and those using tenofovir disoproxil (26–30%).
Conclusion
Concomitant medicine use is widespread among people living with HIV in Australia. Despite a relatively low prevalence of contraindicated medicines, almost a third received medicines that require close monitoring or dose adjustment.
Keywords: comorbidities, drug interactions, HIV
What is already known about this subject
People living with HIV (PLWH) experience other health conditions earlier in their life course compared with the general population, increasing the likelihood of multimedicine use and potential drug–drug interactions.
Drug–drug interactions are associated with decreased adherence and effectiveness of HIV therapy and possibly increased toxicity.
Different antiretrovirals are associated with a greater likelihood of potential drug–drug interactions, particularly protease inhibitors.
What this study adds
Over 2/3 of PLWH in Australia use medicines in addition to their antiretroviral therapy, especially systemic anti‐infectives (e.g., amoxicillin, valaciclovir) and medicines acting on the nervous system (e.g., diazepam, paracetamol + codeine).
About 1/3 of PLWH in Australia use 5 or more medicines in addition to their antiretroviral therapy within the year, increasing to 39% among people aged 50 years or older.
Among people who are using concomitant medicines in addition to their antiretroviral therapy, almost 1/3 use medicines that require close monitoring or dose adjustment, and 5% use contraindicated medicines.
A high rate of contraindications or interactions requiring close monitoring/dose adjustment occurred among people treated with protease inhibitors (50–73%), non‐nucleoside reverse transcriptase inhibitors (35–64%), or single‐tablet combinations containing elvitegravir (30–46%).
1. INTRODUCTION
Lifetime antiretroviral therapy (ART) is recommended for all people following HIV diagnosis, preventing disease progression, improving quality of life and eliminating HIV transmission risk when users achieve undetectable viral load. 1 In Australia, over 28 000 people take daily ART for HIV treatment, with approximately half of those aged over 50 years. 2 As the number of ART‐treated people and survival have increased, concerns have been raised about the impact of comorbid disease treatment on HIV outcomes. 3 , 4 , 5
People living with HIV (PLWH) experience non‐AIDS conditions earlier in their life course, 6 increasing the likelihood of concomitant medicine use and drug–drug interactions (DDIs). Previous studies have shown that approximately 68–91% of PLWH use at least 1 medicine in addition to their antiretrovirals and 23–47% take at least 5 other medicines. 7 , 8 , 9 , 10 , 11 Consequently, potential DDIs occur in over 2/3 of people on ART. 9 , 10 , 12
Drug interactions with ART are common, potentially serious, often overlooked and present a challenge to the clinical management of HIV. 13 These interactions may occur during absorption, metabolism, or elimination of antiretrovirals and other medicines. 13 Most interactions occur because commonly used ART include potent inhibitors of cytochrome P450 metabolic pathways and/or intestinal transporters that improve pharmacokinetics of other antiretrovirals (e.g., cobicistat, ritonavir) and allow daily dosing. 13 Other ART combinations include antiretrovirals with potentially additive renal, bone or other metabolic toxicity. 13 Drug interactions are associated with adverse clinical outcomes, such as increased toxicity, decreased adherence to ART, decreased ART effectiveness and emergence of drug resistance. 10 , 14 , 15 The patterns of these interactions vary by ART regimen; thus, selecting the ART regimen considering patient's comorbidities to reduce the probability of interactions may optimize treatment. Although there are some data on multimedicine use and ART interactions, 9 , 10 , 11 , 16 population‐level estimates of concomitant medicine use, polypharmacy and drug‐interactions are scarce 7 and likely to be sensitive to differences in the prevalence of comorbidities and ART use profiles across health jurisdictions.
In this population‐based study, we quantify concomitant use of medicines in people dispensed ART in Australia, estimate the occurrence of potential drug‐to‐drug interactions and identify ART regimens associated with clinically relevant drug‐to‐drug interactions.
2. METHODS
This study was approved by the New South Wales Population and Health Services Research Ethics Committee (Approval Number: 2013/11/494) and data access was granted by the Services Australia External Request Evaluation Committee (MI10477).
2.1. Study design
We conducted a cohort study of all people dispensed ART listed on Australia's Pharmaceutical Benefits Scheme (PBS). The PBS data collection contains individual‐level data on medicine dispensing history for all Australian residents entitled to subsidized access to prescribed medicines. The PBS dataset contains information on the medicine dispensed, including the PBS item code, date of supply, date of prescription and quantity dispensed. This data collection does not include antiretrovirals prescribed to public hospital inpatients, obtained through compassionate access or clinical trials or paid in full by users. 17
We used a 10% random sample of PBS‐eligible people (PBS 10% sample), extracted based on the individual's randomly assigned unique ID. We used similar methods as those described previously. 18 Briefly, we included all people aged ≥18 years dispensed at least 3 antiretroviral agents in a 30‐day window between 1 January 2018 and 31 December 2019 or dual therapy composed of dolutegravir plus rilpivirine or lamivudine, or darunavir boosted with ritonavir plus raltegravir or lamivudine (see Box A1 for the full list of antiretrovirals). We defined cohort characteristics at the time of their first ART dispensing during the study period, including sex, age, components of the ART regimen, ART class, ART regimen type (single or multitablet) and treatment status (naïve or experienced) based on a 3‐year lookback to determine previously observed dispensing of at least 1 antiretroviral.
2.2. Outcomes of interest
We assessed nontopical medicines dispensed to the cohort within 1 year of their first ART dispensing, excluding formulations such as shampoos, creams, ointments and eye/ear drops. We excluded topical medicines as few are absorbed systemically and are less likely to cause DDIs with antiretrovirals (see Box A2 for details). ART is used continuously and 75% of the cohort were dispensed antiretrovirals within 107 days of their previous ART dispensing. Therefore, we defined concomitant medicine use as the dispensing of any non‐ART medicine within each 90‐day interval from an antiretroviral dispensing. 19
We identified potential DDIs between antiretrovirals and concomitant medicines using the University of Liverpool HIV drug interactions database API tool. 20 As PBS coding standards differed from the Liverpool database, we harmonized the two datasets to allow mapping the medicines. We disaggregated dispensing records of non‐ART medicines containing a combination of active ingredients to each component separately (e.g., a dispensing of amoxicillin + clavulanic acid was disaggregated into one record for amoxicillin and another for clavulanic acid). We further disaggregated the following ART combinations: tenofovir disoproxil + emtricitabine + efavirenz, abacavir + lamivudine, abacavir + lamivudine + zidovudine, lamivudine + zidovudine. Then, for every antiretroviral and non‐ART pair, we classified the potential effects of the DDI based on the University of Liverpool HIV Drug Interaction system classification, including medicines that should not be coadministered; medicines with potential interaction that requires close monitoring, alteration of dosage or timing of administration; medicines with potential weak interaction with unlikely need for dosage alteration; and medicines without clinically significant interaction.
2.3. Statistical analysis
We reported the number and percentage of people dispensed at least 1 and at least 5 concomitant non‐ART medicines within 1 year by age group (18–34 years, 35–49 years, ≥50 years) and sex (female, male). We also reported the number and percentage of people dispensed concomitant non‐ART medicines by medicine and medicine class according to age group (18–49 years, ≥50 years). To estimate the number of concomitant non‐ART medicines used by each person within a 1‐year period of the first observed ART dispensing, we counted the number of unique non‐ART medicines dispensed in all the 90‐day intervals from each ART dispensing period.
We then reported the number and proportion of people using non‐ART concomitant medicines according to medicine and medicine class and type of DDI (unknown, not relevant, weak interaction, monitor/adjust or do not coadminister). We identified the top 10 most common non‐ART medicines and the concomitant antiretrovirals used by type of DDI, focusing only on possible relevant interactions (weak interaction, monitor/adjust or do not coadminister). For this analysis we classified the concomitant antiretroviral formulation by regimens containing enhancers and antiretrovirals commonly involved in DDIs: boosted integrase strand transfer inhibitor (INSTI), boosted protease inhibitor, other cytochrome P450 (3A4, 2D6, 2C9, 2C19) inhibitor (i.e., efavirenz, etravirine and the protease inhibitors atazanavir, darunavir, fosamprenavir, indinavir, saquinavir and tipranavir) or other antiretroviral.
Finally, we reported the number and percentage of people with at least 1 interaction that required a dosage adjustment and/or close monitoring or a combination that is contraindicated according to the antiretrovirals formulations used.
All statistical analysis were performed using SAS v.9.4 and R software 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria).
3. RESULTS
We identified 2230 people dispensed ART between Jan 2018 and Dec 2019 (see Figure S1). Most people were male (87.7%), the mean age was 49.0 years (standard deviation 12.4), and approximately half of the cohort was aged 50 years or older (50.5%, median = 50 years, IQR 40–57 years). A large proportion of people were dispensed a single‐tablet regimen (57.6%), used the backbone of two nucleoside reverse transcriptase inhibitors plus an INSTI (42.6%) or boosted INSTI (22.0%), and were treatment experienced (89.8%) at the time of the first observed ART dispensing in the study period (Table 1). Most common regimens at first dispensing were abacavir + lamivudine + dolutegravir (n = 525, 23.5%), tenofovir alafenamide + emtricitabine + elvitegravir/cobicistat (n = 470, 21.1%), tenofovir alafenamide + emtricitabine + dolutegravir (n = 234, 10.5%), tenofovir alafenamide + emtricitabine + rilpivirine (n = 175, 7.9%) and tenofovir disoproxil + emtricitabine + efavirenz (n = 118, 5.3%).
TABLE 1.
Cohort characteristics, Australia 2018–2019 (n = 2230)
| Baseline characteristics | n (%) |
|---|---|
| Sex | |
| Female | 275 (12.3) |
| Male | 1955 (87.7) |
| Age group (years) | |
| 18–34 | 306 (13.7) |
| 35–49 | 797 (35.8) |
| 50–64 | 884 (39.6) |
| 65 or above | 243 (10.9) |
| ART type | |
| Single‐tablet regimen | 1172 (57.6) |
| Multi‐tablet regimen | 1058 (47.4) |
| ART regimens | |
| 2 NRTI + integrase strand transfer inhibitors | 949 (42.6) |
| 2 NRTI + boosted integrase strand transfer inhibitors | 490 (22.0) |
| 2 NRTI + non‐nucleoside reverse transcriptase inhibitors | 469 (21.0) |
| 2 NRTI + protease inhibitors or boosted protease inhibitors | 84 (3.8) |
| 2 NRTI + integrase strand transfer inhibitors + protease inhibitors or boosted protease inhibitors | 80 (3.6) |
| Entry inhibitors and/or etravirine‐based regimens | 54 (2.4) |
| Other | 104 (4.7) |
| Treatment status | |
| Naïve | 228 (10.2) |
| Experienced | 2002 (89.8) |
Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside/nucleotide reverse transcriptase inhibitors.
3.1. Concomitant medicine use
A total of 1728 (77.5%) people were dispensed at least 1 medicine within 90 days of their ART; 633 (28.4%) had 5 or more unique medicines dispensed over multiple 90‐day intervals of antiretroviral dispensing within 1 year (Figure 1, Table 2). Overall, the median number of concomitant medicines was 3 (IQR 2, 6), increasing to 4 (IQR 2, 7) among people aged ≥50 years.
FIGURE 1.
Number of unique non‐ART medicines dispensed within 90 days of an ART dispensing over the year, stratified by age group and sex, Australia (n = 2230). ART: antiretroviral therapy
TABLE 2.
Most prevalent nonantiretroviral therapy concomitant medicines according to the Anatomical Therapeutical Classification group class and age group as a percentage of comedicated people, Australia (n = 1178)
| Rank | Overall (n = 1728) | 18–49 years (n = 769) | 50+ years (n = 959) | |||
|---|---|---|---|---|---|---|
| Concomitant medicine | n (%) | Concomitant medicine | n (%) | Concomitant medicine | n (%) | |
| 1 | Anti‐infectives for systemic use | 1168 (68) | Anti‐infectives for systemic use | 541 (70) | Anti‐infectives for systemic use | 627 (65) |
| Amoxicillin + clavulanic acid | 311 (18) | Amoxicillin + clavulanic acid | 150 (20) | Valaciclovir | 165 (17) | |
| Amoxicillin | 270 (16) | Amoxicillin | 131 (17) | Amoxicillin + clavulanic acid | 161 (17) | |
| Valaciclovir | 253 (15) | Cephalexin | 112 (15) | Amoxicillin | 139 (14) | |
| 2 | Nervous system | 965 (56) | Nervous system | 409 (53) | Nervous system | 556 (58) |
| Diazepam | 217 (13) | Diazepam | 108 (14) | Paracetamol + codeine | 114 (12) | |
| Paracetamol + codeine | 198 (11) | Paracetamol + codeine | 84 (11) | Diazepam | 109 (11) | |
| Temazepam | 155 (9) | Oxycodone | 67 (9) | Temazepam | 97 (10) | |
| 3 | Cardiovascular system | 681 (39) | Alimentary tract and metabolism | 145 (19) | Cardiovascular system | 541 (56) |
| Rosuvastatin | 258 (15) | Pantoprazole | 33 (4) | Rosuvastatin | 210 (22) | |
| Atorvastatin | 111 (6) | Esomeprazole | 32 (4) | Atorvastatin | 99 (10) | |
| Perindopril | 98 (6) | Metoclopramide | 29 (4) | Perindopril | 83 (9) | |
| 4 | Alimentary tract and metabolism | 516 (30) | Cardiovascular system | 140 (18) | Alimentary tract and metabolism | 371 (39) |
| Esomeprazole | 134 (8) | Rosuvastatin | 48 (6) | Esomeprazole | 102 (11) | |
| Pantoprazole | 134 (8) | Perindopril | 15 (2) | Pantoprazole | 101 (11) | |
| Metformin | 87 (5) | Propranolol | 13 (2) | Metformin | 68 (7) | |
| 5 | Musculoskeletal system | 299 (17) | Musculoskeletal system | 103 (13) | Musculoskeletal system | 196 (20) |
| Meloxicam | 75 (4) | Ibuprofen | 26 (3) | Meloxicam | 59 (6) | |
| Celecoxib | 56 (3) | Celecoxib | 19 (2) | Celecoxib | 37 (4) | |
| Ibuprofen | 40 (2) | Diclofenac | 19 (2) | Naproxen | 24 (3) | |
The percentage of people dispensed concomitant medicines increased with age, from 62% (n = 190) among those aged 18–34 years to 85% (n = 1959) among people aged ≥50 years. Thirty‐nine per cent (n = 445) of people aged ≥50 years were dispensed 5 or more unique medicines over the year, compared to 11% (n = 35) people aged 18–34 years. These findings were similar by sex (Figure 1).
The ranking of the most common classes of medicines dispensed among comedicated people was mostly similar across age groups, with nuances in the leading concomitant medicine in each age group (Table 2). Anti‐infectives for systemic use were the most common medicine class dispensed, being used by approximately 65–70% of people across age groups. The leading medicines in this class were antibiotics and non‐ART antivirals (e.g., amoxicillin, valaciclovir). Another 53–58% of people were dispensed medicines acting on the nervous system, mostly benzodiazepines and opioid analgesics. Among people aged 50 years or older, a large proportion was dispensed cardiovascular medicines (56%), particularly statins and antihypertensives. Compared with the younger age group (18–49 years), they were also more likely to be dispensed medicines acting on the alimentary tract and metabolism (39 vs. 19%), such as proton pump inhibitors and metabolism and musculoskeletal system (20 vs. 13%), such as nonsteroidal anti‐inflammatory drugs.
3.2. Drug to drug interactions
Among comedicated people, 1664 (96%) had combinations with potential DDIs (Figure 2, Tables 3 and 4). A total of 1637 (95%) people had at least 1 weak interaction, 558 (32%) had at least 1 interaction requiring close monitoring/adjustment and 94 (5%) received medicines that should not be coadministered. Rates of potential DDIs over the year were similar across age groups: 97% (929/959) for people aged ≥50 years and 95% for people aged 18–49 years (735/769).
FIGURE 2.
Unique nonantiretroviral therapy concomitant medicines used by the study population according to the Anatomical Therapeutical Classification group and type of potential drug–drug interaction, Australia (n = 1178). Individuals can be counted more than once in each category if receiving multiple unique medicines with different types of drug–drug interactions, ART: Antiretroviral therapy
TABLE 3.
Top 10 most common nonantiretroviral therapy medicines used among people experiencing potentially clinically relevant drug–drug interactions (DDIs) by interaction type and antiretrovirals dispensed
| Antiretroviral formulation used associated with the DDI (n) | ||||||
|---|---|---|---|---|---|---|
| Rank | Medicine | Boosted‐integrase strand inhibitor | Boosted‐protease Inhibitor | Other cytochrome P450 (3A4, 2D6, 2C9, 2C19) inhibitor | Other antiretroviral | n persons (%) |
| Do not coadminister | 94 (100) | |||||
| 1 | Budesonide a | Elvitegravir/c (15) | Ritonavir (4), Darunavir/c‡ | Atazanavir b | ‐ | 21 (22) |
| 2 | Clopidogrel | Elvitegravir/c (6) | Ritonavir (7) | Atazanavir b | ‐ | 15 (16) |
| 3 | Fluticasone a | Elvitegravir/c (8) | Ritonavir b , Darunavir/c b | Atazanavir b (4), Indinavir | ‐ | 14 (15) |
| 4 | Esomeprazole | ‐ | Atazanavir/c b | Atazanavir (5) | Rilpivirine (5) | 11 (12) |
| 5 | Pantoprazole | ‐ | ‐ | Atazanavir | Rilpivirine (7) | 9 (10) |
| 6 | Quetiapine | Elvitegravir/c (3) | Atazanavir/c b , ritonavir b | Atazanavir | ‐ | 7 (7) |
| 7 | Simvastatin | Elvitegravir/c b | Ritonavir b , Atazanavir/c b , Lopinavir/r b | ‐ | ‐ | 5 (5) |
| 8 | Amiodarone | Elvitegravir/c b | Ritonavir b | ‐ | ‐ | 3 (3) |
| 9 | Apixaban | Elvitegravir/c b | Ritonavir b | Atazanavir b | ‐ | 3 (3) |
| 10 | Domperidone | Elvitegravir/c b | Ritonavir b | Atazanavir b | ‐ | 3 (3) |
| Close monitor/adjustment | 558 (100) | |||||
| 1 | Oxycodone | Elvitegravir/c (47) | Ritonavir (14), Darunavir/c (5), Atazanavir/c (3) | Efavirenz (12), Atazanavir (6), Etravirine (3) | Nevirapine (11) | 90 (16) |
| 2 | Diazepam | Elvitegravir/c (46) | Ritonavir (9), Darunavir/c (6), Atazanavir/c (4) | Atazanavir (6), Efavirenz (4), Etravirine (4) | Nevirapine (10) | 77 (14) |
| 3 | Metformin | Elvitegravir/c (16) | Darunavir/c (4), Atazanavir/c (1) | ‐ | Dolutegravir (27), Bictegravir b | 57 (10) |
| 4 | Amlodipine | Elvitegravir/c (20) | Ritonavir (7), Darunavir/c (3), Atazanavir/c b | Efavirenz (6), Etravirine (4), Atazanavir b | Nevirapine (15) | 54 (10) |
| 5 | Rosuvastatin | ‐ | Ritonavir (31), Darunavir/c (9), Atazanavir/c b | Atazanavir (8) | ‐ | 45 (8) |
| 6 | Atorvastatin | Elvitegravir/c (20) | Ritonavir (10), Darunavir/c b , Atazanavir/c b , Lopinavir/r b | Efavirenz (8), Atazanavir b | ‐ | 42 (8) |
| 7 | Mirtazapine | Elvitegravir/c (21) | Ritonavir (4), Darunavir/c (3) | Efavirenz (4), Atazanavir (3) | Nevirapine (8) | 40 (7) |
| 8 | Prednisolone | Elvitegravir/c (17) | Ritonavir (8), Darunavir/c b | Efavirenz (4), Atazanavir b , Etravirine b | Nevirapine (4) | 35 (6) |
| 9 | Clarithromycin | Elvitegravir/c (12) | Ritonavir b , Darunavir/c b | Efavirenz b , Etravirine b | Tenofovir (12), Nevirapine b , Tenofovir + rilpivirine b | 29 (5) |
| 10 | Valaciclovir | ‐ | ‐ | ‐ | Tenofovir (29) | 29 (5) |
| Weak interaction | 1637 (100) | |||||
| 1 | Amoxicillin | 125 | 49 | 51 | 625 | 515 (31) |
| 2 | Clavulanic acid | 69 | 25 | 31 | 369 | 304 (19) |
| 3 | Rosuvastatin | 68 | ‐ | 30 | 380 | 265 (16) |
| 4 | Valaciclovir | 54 | 32 | 34 | 322 | 251 (15) |
| 5 | Cefalexin | 46 | 26 | 28 | 290 | 242 (15) |
| 6 | Paracetamol | 53 | 22 | 10 | 272 | 221 (14) |
| 7 | Diazepam | ‐ | ‐ | ‐ | 275 | 169 (10) |
| 8 | Doxycycline | 45 | 18 | 4 | 190 | 166 (10) |
| 9 | Codeine | ‐ | ‐ | <3 | 232 | 158 (10) |
| 10 | Temazepam | 30 | 21 | 15 | 200 | 153 (9) |
People can be dispensed multiple antiretrovirals interacting with the same medicine within the same or across multiple potential drug interaction categories.
Abbreviation: c, cobicistat.
Medicines administered mostly via inhalation. Less than 1% of budesonide dispensings were for rectal use.
For privacy reasons, we used consequential cell suppression for small numbers (<3).
TABLE 4.
Percentage of people on each antiretroviral dispensed medicines that should not be coadministered, require close monitoring or dose adjustment
| Antiretroviral | Number of people with DDIs/number of people using that ART (%) |
|---|---|
| Protease inhibitors | |
| Atazanavir | 32/44 (72.7) |
| Atazanavir + cobicistat | 13/17 (76.5) |
| Ritonavir | 72/107 (67.3) |
| Darunavir + cobicistat | 31/50 (62.0) |
| Lopinavir + ritonavir | 3/6 (50.0) |
| Non‐nucleoside reverse transcriptase inhibitors | |
| Efavirenz | 59/92 (64.1) |
| Etravirine | 21/35 (60.0) |
| Nevirapine | 65/116 (56.0) |
| Rilpivirine | 7/20 (35.0) |
| Nucleoside and nucleotide reverse transcriptase inhibitors | |
| Tenofovir disoproxil | 30/103 (29.1) |
| Tenofovir disoproxil + emtricitabine | 23/87 (26.4) |
| Zidovudine | 4/15 (26.7) |
| Abacavir | 3/90 (3.3) |
| Tenofovir alafenamide + emtricitabine | 12/413 (2.9) |
| Lamivudine | <3/125 (<1.0) |
| Integrase strand transfer inhibitors | |
| Dolutegravir | 26/309 (8.4) |
| Raltegravir | 4/166 (2.4) |
| Entry inhibitors | |
| Maraviroc | 3/23 (13.0) |
| Other combinations | |
| Tenofovir alafenamide + emtricitabine + elvitegravir + cobicistat | 188/408 (46.1) |
| Tenofovir disoproxil + emtricitabine + elvitegravir + cobicistat | 3/10 (30.0) |
| Tenofovir alafenamide + emtricitabine + rilpivirine | 43/162 (26.5) |
| Dolutegravir + rilpivirine | 4/17 (23.5) |
| Dolutegravir + abacavir + lamivudine | 46/433 (10.6) |
| Tenofovir alafenamide + emtricitabine + bictegravir | <3/93 (<1.5) |
Note: For privacy reasons, we used consequential cell suppression for small numbers (<3).
A high number of clinically relevant potential DDIs were identified among people receiving the most common therapeutic classes (i.e., anti‐infectives for systemic use, medicines acting on the nervous system and cardiovascular medicines). However, considering the number of people receiving medicines from each therapeutic class, potential DDIs occurred more often for people receiving systemic hormonal preparations (89%), such as corticosteroids for systemic use (e.g., prednisolone, prednisone, dexamethasone) or thyroid therapy (e.g., levothyroxine); antiparasitics (89%), such as atovaquone and praziquantel; medicines acting on the alimentary tract and metabolism (83%), such as proton pump inhibitors (e.g., esomeprazole, pantoprazole) or blood glucose lowering agents (e.g., metformin, gliclazide); cardiovascular system (82%), such as statins (e.g., rosuvastatin, atorvastatin) or antihypertensives (e.g., perindopril, amlodipine); blood and blood forming organs (81%), such as antithrombotic agents (e.g., clopidogrel, apixaban) or antianaemic preparations (e.g., hydroxocobalamin, folic acid); and genitourinary system and sex hormones (80%), such as urologicals (e.g., tamsulosin, dutasteride) and sex hormones (e.g., testosterone, levonorgestrel, ethinyloestradiol; Figure 2). Table 3 depicts the medicines most involved in potentially clinically relevant DDIs as a percentage of people experiencing each DDI type. Budesonide (inhalation), clopidogrel and fluticasone (inhalation) were the leading medicines that should not be coadministered (see the full list of DDIs interactions with medicines that should not be coadministered in Table S1). Oxycodone, diazepam and metformin were the leading among medicines requiring close monitoring or dose adjustment and amoxicillin, clavulanic acid and rosuvastatin were the most commonly associated with weak interactions. DDIs interactions with medicines that should not be coadministered or requiring close monitoring or dose adjustment were commonly associated with the use of boosted regimens and antiretroviral inhibiting cytochrome P450 enzymes.
Approximately 1/2 to almost 3/4 of people receiving protease inhibitors were estimated to have had at least one potential contraindication or interactions requiring close monitoring/dose adjustment. This was followed by people using non‐nucleoside reverse transcriptase inhibitors, particularly efavirenz (64%), people using combinations containing elvitegravir (30–46%) and those using tenofovir disoproxil (26–30%; Table 4).
4. DISCUSSION
In this nationwide study, we identified over 2/3 of PLWH in Australia use medicines concomitantly to their ART, particularly people aged 50 years or above. Although the use of contraindicated prescriptions was modest (5%), and within the range prior reported in the literature, 9 , 10 , 11 these interactions are potentially serious and almost 1/3 of comedicated people received medicines that require potential dose adjustment and/or close monitoring. Systemic anti‐infectives and medicines acting on the nervous system were the medicine classes most used in our cohort, but relevant potential DDIs occurred more often among people receiving systemic hormonal preparations (excluding sex hormones) or antiparasitics. PLWH treated with ritonavir or cobicistat boosted protease or integrase inhibitors experienced clinically relevant DDIs (i.e., requiring monitoring/dose adjustment or contraindications) more often than people on other regimens. Contrastingly, people treated with integrase inhibitor regimens experienced the lowest rates of clinically relevant DDIs.
DDIs pose a particular challenge for clinical management of HIV, as our results show. The commonest contraindicated interactions were with inhaled steroids budesonide and fluticasone with a potential for life‐threatening adrenal insufficiency and Cushing syndrome. 21 Other common contraindicated interactions involved the use of protease inhibitors with medicines for cardiovascular disease prevention and control: protease inhibitors may increase bleeding risk of anticoagulants (e.g., apixaban) and cause insufficient inhibition of platelet aggregation of antiplatelets (e.g., clopidogrel). 15 The commonly used proton‐pump inhibitors (e.g., omeprazole, pantoprazole) may also decrease rilpivirine plasma levels by 40%, reducing ART effectiveness. 15 Overall, antiretroviral agents known to cause frequent and serious DDIs are often prescribed in a specialist environment 22 while medicines that cause concerning interactions are commonly prescribed in primary care or available over the counter (e.g., fluticasone for allergic rhinitis). In many cases, the prescribing doctor or the dispensing pharmacist may be unaware of the interaction or even unaware that the person is taking ART given people may voluntarily withhold this information due to privacy or discrimination concerns. It is also possible the ARV prescriber chose to prescribe the comedication in despite the contraindication.
Although conflicting results have been reported, 23 PLWH can receive a higher number of medicines 13 , 24 , 25 and be more often on polypharmacy 8 , 13 , 25 compared to the general population, increasing their risk of potential DDI. PLWH have higher risk of developing several comorbidities, such as myocardial infarction (risk ratio: 1.73, 95% confidence interval [CI] 1.44 to 2.08) 26 diabetes (adjusted odds ratio [aOR]: 1.97, 95%CI 1.04 to 3.75), 27 thrombosis (aOR: 3.08, 95%CI 1.36 to 6.98), 27 and neuropathy (aOR: 34.6, 95%CI 8.9 to 134.5), 27 among others 25 , 27 resulting from a combination of persistent immune activation and viral infections, use of substances (e.g., tobacco, alcohol or drugs), and antiretroviral toxicity. 13 As expected, we observed higher use of concomitant medicines among older people, probably due to a greater number of comorbidities in this group. We also found nuances in medicine classes used by age, with markedly higher use of cardiovascular and acid‐related disorders medicines among older people. 7 , 12 , 28 , 29 Despite increasing age being one of the key factors for increased cardiovascular risk, these differences can also be due to prolonged exposure to ART, particularly for specific ART classes (e.g., protease inhibitors) and antiretrovirals (e.g., abacavir). 26
The profile of concurrent medicines identified in our study was mostly consistent with prevalent acute conditions and comorbidities in PLWH in Australia. Antibiotics and antivirals (i.e., amoxicillin, cephalexin, valaciclovir) are indicated mostly for treating episodic infections (e.g., upper respiratory infections), while valaciclovir can also be used for preventing herpes simplex recurrence and shingles; common conditions among PLWH. 7 , 27 , 30 In Australia, the most prevalent chronic conditions in PLWH include depression (17–38%), 10 , 27 , 31 , 32 anxiety (19–23%), 27 , 31 hypertension (18–44%), 27 other cardiovascular diseases (e.g., heart failure, 9–19%), 10 , 31 neuropathy (22%), 27 cancer (14%) 31 and type 2 diabetes (6–15%). 10 , 27 , 31 Accordingly, we identified medicines to treat those conditions among the top 5 non‐ART concurrent medicines dispensed in our cohort, reflecting an ageing population profile.
Reducing the number of concomitant medicines and avoiding polypharmacy can help avoiding medicine‐related harms. For instance, each additional medicine taken increases the mean number of adverse events by 10%, 33 the risk of hospitalization by 8% and the risk of mortality by 5–11% even after controlling for comorbidities in populations with or without HIV. 23 Multimedicine use has also been associated with suboptimal adherence to ART, 34 possibly impairing treatment outcomes. However, these dose–response associations should not prevent PLWH from receiving optimal care, with further research to guide deprescribing strategies in the context of multimorbidity and multimedicine use needed. 23 Of note, we observed that over 1/3 of people using single‐tablet regimens containing elvitegravir had contraindications or interactions requiring close monitoring/dose adjustment and this ART combination is commonly used. 18 However, other single‐tablet regimens with better drug interaction profiles are available in Australia and could potentially be indicated as the preferred therapy among people with comorbidities.
Managing chronic comorbidities has been identified as one of the main challenges Australian medical practitioners face in HIV care, and one of the main reasons for switching ART. 22 Understanding the mechanism of interactions between other medicines and antiretrovirals can help prescribers in assessing the risk of DDIs and multimedicine harm. While providing high level recommendations in clinical guidelines regarding the medicine‐classes most involved in DDIs is useful, periodic review of prescribed and over‐the‐counter medicines, including supplements and herbal treatments, and the use of dual therapy may be better ways to avoid these harms. Tools such as the University of Liverpool interaction checker, Hivclinic.ca, Webmd.com and Drugs.com are freely available and should be used when prescribing or reviewing concomitant medicines and ART. The first two tools also provide information of potential DDIs between ART and recreational drugs.
The proportion of potential DDIs is expected to decrease with the introduction of dual therapy regimens in Australia for both treatment naïve and experienced PLWH, 21 with dolutegravir and lamivudine being among regimens with lowest rates of relevant potential DDIs in our study. The availability of long‐acting antiretroviral injectables and implants in the future may also contribute to the use of safer ART. By avoiding gastrointestinal absorption, those formulations will lack DDIs from acid reduction or chelation, remaining the challenges rising from renal and hepatic metabolization of antiretrovirals. 13 , 35
4.1. Strengths and limitations
This study has several limitations. We probably underestimated concurrent medicine use and potential DDIs given PBS data does not capture medicines privately purchased, over the counter medicines or medicines dispensed for public inpatients. 17 We also did not have information on the DDI profile of approximately 50 medicines used by our study population (see Box A3 for details). Because PBS data also do not capture the supply days for each dispensing, we used the interval between ART and other dispensings to define concomitant medicine use (90 days), a period commonly used in the literature. 25 Due to the nature of our data source, we also did not have access to health outcomes related to potential DDI. Finally, we assumed medicines dispensed are consumed by people. Despite those limitations, we characterized patterns of concurrent medicine use and potential DDIs using population‐wide data, provide baseline information for investigations assessing the reasons for using contraindicated concomitant medicines and focussed on deprescribing strategies among PLWH. The knowledge of the common medicines used will help ensure prescribing guidelines are relevant and up to date, leading to improved care for PLWH.
5. CONCLUSION
Concomitant medicine use is high among PLWH in Australia on antiretroviral therapy and a high proportion of people receive medicines that require close monitoring or dose adjustment. Patterns of interactions vary by ART regimen and occur even among people on novel single‐tablet regimens. Selecting regimens based on patient's comorbidities and concurrent medicines is key to optimizing treatment.
COMPETING INTERESTS
The Liverpool Human Immunodeficiency Virus Drug Interactions Resource receives support from Gilead Sciences, ViiV Healthcare, Merck, and Janssen but the editorial content remains independent. SAP is a member of the Drug Utilisation Sub Committee of the Pharmaceutical Benefits Advisory Committee. The views expressed in this paper do not represent those of the Committee. In 2020, the Centre for Big Data Research in Health, UNSW Sydney has received funding from AbbVie Australia to conduct post‐market surveillance research. AbbVie did not have any knowledge of, or involvement in, the current study.
CONTRIBUTORS
J.O.C., S.P. and A.S. conceived of and designed the study. S.P. and S.G. acquired the data. J.O.C. and S.L. analysed the data. All authors contributed to interpretation of the results. J.O.C. and A.S. drafted the manuscript. All authors revised the manuscript and approved the final manuscript version.
Supporting information
FIGURE S1. Diagram of cohort selection
TABLE S1. Proportion of people using concomitant medicines that should not be coadministered due to potential severe drug–drug interactions (n = 94)*
ACKNOWLEDGEMENTS
We thank the Australian Government Services Australia for supplying the data and the staff of the Department of Pharmacology, University of Liverpool, UK. Open access publishing facilitated by University of New South Wales, as part of the Wiley ‐ University of New South Wales agreement via the Council of Australian University Librarians.
APPENDIX A.
BOX A1.
Antiretroviral medicines in the Pharmaceutical Benefits Scheme (PBS) by generic name and item code
| Generic drug name | PBS item code |
|---|---|
| Abacavir | 05601T, 05602W, 06264Q, 06265R, 10294T, 10356C |
| Abacavir + lamivudine | 05603X, 06458X, 10357D, 11 246X |
| Abacavir + lamivudine + zidovudine | 05604Y, 06327B, 10305J |
| Amprenavir | 06333H, 06334J |
| Atazanavir | 05612J, 05613K, 05614L, 05615M, 06451M, 06452N, 09614B, 09646Q, 10276W, 10321F, 10349Q, 11 657M |
| Atazanavir + cobicistat | 10692R |
| Bictegravir + emtricitabine + tenofovir alafenamide | 11649D |
| Darunavir | 02980W, 03392M, 05000E, 05652L, 05653M, 05821J, 05823L, 09581G, 09616D, 10000H, 10287K, 10329P, 10367P, 12110J, 12111K |
| Darunavir + cobicistat | 10903W |
| Darunavir + cobicistat + emtricitabine + tenofovir alafenamide | 11955F |
| Delavirdine | 05659W, 06243N |
| Didanosine | 05663C, 05664D, 05665E, 05666F, 06115W, 06116X, 06117Y, 06118B, 06119C, 06298L, 06299M, 06300N, 06301P, 10313T, 10350R, 10351T, 10364L |
| Dolutegravir | 10065R, 10070B, 10283F |
| Dolutegravir + abacavir + lamivudine | 10247H, 10248J, 10345L |
| Dolutegravir + lamivudine | 11843H |
| Dolutegravir + rilpivirine | 11540J |
| Efavirenz | 05706H, 05707J, 05708K, 06258J, 06259K, 06260L, 06283Q, 06356M, 06372J, 09618F, 10275T, 10336B, 10366N |
| Emtricitabine | 05709L, 06137B, 10274R |
| Emtricitabine + rilpivirine + tenofovir alafenamide | 11104K |
| Enfuvirtide | 05710M, 06455R, 10365M |
| Etravirine | 05062K, 05084N, 05736X, 09639H, 10301E |
| Fosamprenavir | 05745J, 05746K, 06453P, 06454Q, 10337C, 10368Q |
| Indinavir | 05752R, 06201J, 06202K, 06252C, 06344X, 10363K |
| Lamivudine | 05770Q, 05771R, 05772T, 05773W, 05774X, 06193Y, 06194B, 06257H, 06271C, 06435Q, 10311Q, 10315X, 10320E, 10338D, 10348P |
| Lamivudine + zidovudine | 05775Y, 06234D, 10284G |
| Lopinavir + ritonavir | 05789Q, 05790R, 05791T, 06340Q, 06341R, 06495W, 09633B, 10272P, 10285H, 10327M |
| Maraviroc | 05792W, 05793X, 09572T, 09573W, 10318C, 10355B |
| Nelfinavir | 06230X, 06231Y, 06331F |
| Nevirapine | 01129K, 01132N, 06215D, 09506H, 09507J, 09571R, 10303G, 10304H, 10319D |
| Raltegravir | 02736B, 02743J, 02754Y, 02760G, 09523F, 09629T, 10286J, 10299C, 10326L, 11248B |
| Rilpivirine | 01170N, 01173R, 10298B |
| Ritonavir | 06203L, 06235E, 06494T, 09542F, 09543G, 09660K, 09677H, 10273Q, 10300D |
| Saquinavir | 06199G, 06248W, 06498B, 09545J, 10335Y |
| Stavudine | 06185M, 06186N, 06189R, 06190T, 06250Y, 09552R, 09553T, 09554W, 09556Y, 10271N, 10312R, 10325K |
| Tenofovir | 06358P, 09563H, 10310P, 11142K, 11155D |
| Tenofovir disoproxil | 11978K, 11982P, 11992E |
| Tenofovir + emtricitabine | 06468K, 09564J, 10347N, 10946D, 10966E, 11146P, 11149T |
| Tenofovir alafenamide + emtricitabine | 11099E, 11 113X |
| Tenofovir disoproxil + emtricitabine | 12506F |
| Tenofovir + emtricitabine for pre‐exposure prophylaxis | 11306C, 12542D, 11276L, 11296M |
| Tenofovir + emtricitabine + efavirenz | 09565K, 09650X, 10297Y |
| Tenofovir + emtricitabine + elvitegravir + cobicistat | 10085T, 10088Y, 10307L, 10680D |
| Tenofovir + emtricitabine + rilpivirine | 01490K, 01491L, 10314W |
| Tenofovir alafenamide + emtricitabine + elvitegravir + cobicistat | 11114Y |
| Tenofovir disoproxil + emtricitabine + efavirenz | 11732L |
| Tipranavir | 09567M, 09610T, 09656F, 09676G, 10344K |
| Zaltacibine | 06149P, 06150Q |
| Zidovudine | 06153W, 06154X, 06155Y, 09570Q, 09651Y, 09652B, 10266H, 10360G, 10361H |
BOX A2.
Algorithm to exclude topical formulations
|
| Cream, ointment, foam, tincture, gel, shampoo, eye, ear, ocular and synonyms |
|
| Mupirocin, sorbitol, lauryl sulfoacetate sodium, sodium chloride, pneumococcal purified capsular, polysaccharides |
BOX A3.
List of medicines with unknown drug–drug interaction profile
| Aflibercept | Isosorbide mononitrate |
| Alectinib | Ketoprofen |
| Alectinib | Leflunomide |
| Benzatropine | Lurasidone |
| Bethanechol | Macrogol‐3350 |
| Bicalutamide | Methenamine hippurate |
| Bicarbonate | Methoxy polyethylene glycol‐epoetin beta |
| Botulinum toxin type a | Minoxidil |
| Cefaclor | Moclobemide |
| Cefuroxime | Nedocromil |
| Cetrorelix | Nitrazepam |
| Choriogonadotropin alfa | Nivolumab |
| Clostridium botulinum complex | Nizatidine |
| Cortisone | Norfloxacin |
| Crizotinib | Omalizumab |
| Cromoglycate | Palonosetron |
| Darunavir | Pancreatic extract |
| Deferasirox | Pancrelipase |
| Desmopressin | Pembrolizumab |
| Dexamfetamine | Pizotifen |
| Diphenoxylate | Plerixafor |
| Dosulepin | Polylactic acid |
| Epoetin alfa | Risedronate |
| Febuxostat | Roxithromycin |
| Follitropin alfa | Sotalol |
| Ibrutinib | Tetrabenazine |
| Indometacin | Trihexyphenidyl (benzhexol) |
| Infliximab | Ustekinumab |
Not available in the University of Liverpool HIV drug interactions database as of 14 January 2022.
de Oliveira Costa J, Lau S, Medland N, Gibbons S, Schaffer AL, Pearson S‐A. Potential drug–drug interactions due to concomitant medicine use among people living with HIV on antiretroviral therapy in Australia. Br J Clin Pharmacol. 2023;89(5):1541‐1553. doi: 10.1111/bcp.15614
The authors confirm that J.O.C. is the Principal Investigator for this paper. J.O.C. and S.L. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Information This research is supported by the National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Medicines Intelligence (ID: 1196900). A.S. is supported by a NHMRC Early Career Fellowship (ID: 1158763). N.M. is supported by a NHMRC Early Career Fellowship (ID: 1158035).
DATA AVAILABILITY STATEMENT
The PBS 10% sample data were used under licence from the Australian Government Services Australia. Access to these data by other individuals or authorities is not permitted without the express permission of the approving human research ethics committees and data custodians. The Liverpool Human Immunodeficiency Virus Drug Interactions data source can be accessed online at https://www.hiv-druginteractions.org/checker and the database can be accessed using an API tool upon request (https://hivdrugs.docs.apiary.io).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
FIGURE S1. Diagram of cohort selection
TABLE S1. Proportion of people using concomitant medicines that should not be coadministered due to potential severe drug–drug interactions (n = 94)*
Data Availability Statement
The PBS 10% sample data were used under licence from the Australian Government Services Australia. Access to these data by other individuals or authorities is not permitted without the express permission of the approving human research ethics committees and data custodians. The Liverpool Human Immunodeficiency Virus Drug Interactions data source can be accessed online at https://www.hiv-druginteractions.org/checker and the database can be accessed using an API tool upon request (https://hivdrugs.docs.apiary.io).