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\begin{document}

\title{Prescribing issues among older HIV-infected persons in a Mediterranean
cohort: Does the current prevalence give cause for concern?}



\author[1]{Cora Loste}%
\author[1]{José Moltó}%
\author[1]{Núria Pérez}%
\author[1]{Jordi Puig}%
\author[1]{Patricia Echeverría}%
\author[1]{Anna Bonjoch}%
\author[1]{Carmina R.Fumaz}%
\author[1]{Begoña Lemos}%
\author[1]{Carla Estany}%
\author[1]{Bonaventura Clotet}%
\author[1]{Eugènia Negredo}%
\affil[1]{Fundació Lluita Contra la Sida}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
AIM: The main objective was to determine the prevalence of prescribing
issues in HIV-infected subjects [?]65 years according to the Beers and
STOPP/START criteria and drug-drug interactions (Liverpool website).
Secondary objectives were to assess the concordance between Beers and
STOPP/START criteria in our population, and to identify the drugs most
frequently involved in the prescribing issues. METHODS: Cross-sectional
cohort study based on a systematic review of the electronic drug
prescriptions of 91 HIV-infected patients aged [?]65 years. Discrepancies
between prescription criteria were assessed using crosstabs and compared
using the Chi-square test or Fisher exact test. RESULTS: The mean age
was 72.1 (5.6) years, 75.8\% had [?]3 comorbidities, and 59.3\%
polypharmacy. Prescribing issues were identified in 87.9\%; 71.4\% by
STOPP/START and 45.1\% by Beers. Comparing both criteria, 56.9\% of
prescribing issues by STOPP/START were detected by Beers, while 92.5\%
of those detected by the Beers criteria were detected by STOPP/START
(p\textless{}0.001). Orange/red flag interactions were found in 45.1\%:
3 severe (red) in 2 patients (2.2\%). The most frequent drugs involved
in prescribing issues were benzodiazepines (\textgreater{}30\%).
Cobicistat was the drug most frequently involved in interactions
(42.9\%). CONCLUSIONS: The prevalence of prescribing issues among older
HIV-infected persons gives cause for concern, as it is almost 90\%.
Optimization strategies, including a critical review of the treatment
plan, should be implemented in clinical routine by a multidisciplinary
team, in particular in patients with multiple comorbidities and
polypharmacy. The STOPP/START criteria should be recommended for
European populations, since they seem to better detect prescribing
issues.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Aging of the general population reveals a series of challenges that must
be addressed and resolved. This is especially true with respect to
adverse drug reactions (ADRs) in elderly people, including drug-induced
morbidity among patients admitted to hospital, which is a major health
problem. In addition to the effects on the patient, the consequent
increase in health care costs is not inconsiderable. One study estimated
total expenditure on medical care related to the use of potentially
inappropriate medication to be \$7.2 billion in the United States in
2001 {[}1{]}.

Prescribing issues and polypharmacy are risk factors that have been
shown to increase the likelihood of ADRs \textsuperscript{{[}2.3{]}}.

In recent years, several tools have been proposed to help prescribers
detect prescribing errors {[}4-9{]}. The first explicit criteria were
the Beers criteria (1991) {[}10{]}, which recommended detecting
potentially inappropriate medications (PIMs). Despite the widespread use
of these criteria throughout the world and the fact that they were
updated in 2015, their implementation in Europe has been limited for
several reasons: they do not consider specific interactions between
drugs, therapeutic duplication, the potential prescribing omissions
(PPOs) of drugs that are indicated, and the fact that more than 50\% of
drugs are not available in Europe. In addition, PIM has not been
significantly associated with ADRs in older hospitalized patients
according to the Beers criteria {[}11{]}.

Therefore, in Europe, it was necessary to develop new criteria according
to the drugs prescribed in this area. The Screening Tool of Older
Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right
Treatment (START) {[}12{]} criteria were finally published in 2008 by
Gallagher et al in Ireland with the objective of detecting potentially
inappropriate prescribing (PIP) and PPOs. The European Geriatrics
Society contributed significantly to the publication of the criteria in
Spain {[}13{]} in 2009.

Following the publication of the latest versions of the STOPP-START
criteria\textsuperscript{14} and the 2015 revision of the Beers criteria
{[}5,6,10,15{]}, these guidelines are proving to be useful tools, and
research on prescribing issues is growing rapidly. In this sense,
several studies have shown an association between PIP/PPOs and the risk
of ADRs, health-related quality of life, re-hospitalization, and
hospital accident and emergency visits in older community-dwelling
patients {[}16-20{]}. Similarly, there is evidence of a significant
improvement in these variables after application of the criteria.

People living with HIV (PLWH) are aging in countries where effective
antiretroviral therapy (ART) is available {[}21,22{]}, and about 50\% of
HIV-infected patients are currently more than 50 years old in developed
countries. Consequently, patients with multiple comorbidities are
becoming more common in daily practice {[}23{]}. In fact, the percentage
of persons receiving polypharmacy is high in European HIV-infected
cohorts (14-40\%) {[}24-26{]}. In this context, PLWH could be at risk of
prescribing issues. However, despite current knowledge, data on this
topic remain scarce, and published data focus mainly on American
populations {[}27,28{]}. Therefore, we performed a study to assess the
prevalence of prescribing issues in a Mediterranean cohort of
HIV-infected patients aged [?]65 years.

\textbf{MATERIALS AND METHODS}

\emph{Study design and population}

We performed a cross-sectional study based on a systematic review of the
most recent electronic prescriptions confirmed by interviewing all
patients aged [?]65 years belonging to an HIV-infected cohort (Over50
cohort). The Over50 cohort is an ongoing prospective cohort of
chronically HIV-infected people aged [?]50 years consecutively attended in
our unit. All patients receive a comprehensive geriatric assessment
covering medical, psychological, functional, and social aspects. Written
informed consent was obtained from all participants before inclusion.
The trial protocol was reviewed and approved by the clinical research
ethics committee of the Germans Trias i Pujol Hospital
(http://www.ceicgermanstrias.cat/) and met the criteria of the
Declaration of Helsinki and the requirements of Good Clinical Practice
(REF. CEI:~ PI-16-068).





\emph{Study objectives and endpoints}

The main objective of the study was to determine the prevalence of
prescribing issues, including: concomitant medication that had to be
stopped (PIMs according to the BEERS criteria or PIP according to the
STOPP criteria), concomitant medication that the patient should have
been receiving but was not (PPOs according to the STOPP/START criteria),
and/or potential and relevant drug interactions between concomitant
treatment and ART according to the University of Liverpool website (see
definitions below). The secondary objectives included determination of
the concordance between the Beers and the STOPP/START criteria in our
population, as well as identification of the drugs most frequently
involved in the prescribing issues.

\emph{Definitions}

A prescribing issue must fulfill at least 1 criterion from the
STOPP/START and/or Beers criteria and/or be considered a drug-drug
interaction (orange or red flags).

The study was based on the latest version of the STOPP/START criteria
(2015) {[}14{]}, which includes a list of medication classes divided by
sections. Briefly, the STOPP criteria cover potentially inappropriate
drugs in patients aged [?]65 years, namely, any drug prescribed without an
evidence-based clinical indication, any drug prescribed beyond the
recommended duration where treatment duration is well defined, and/or
any duplicate drug class prescription. These criteria also classify
drugs by family, such as antiplatelet/anticoagulant drugs and central
nervous system and psychotropic drugs (see supplementary data of the
reference 14). The START criteria cover vaccines and medications that
patients should take but are not prescribed. These are classified by
systems (e.g., cardiovascular and respiratory systems).

We used the 2015 version of the Beers criteria {[}15{]}, which was drawn
up by an expert panel, includes a list of medications and medication
classes that should be avoided or used with caution in adults aged [?]65
years, and is divided into 5 categories.

The Liverpool University website (www.hiv-druginteractions.org) was used
to identify drug interactions with ART and concomitant medication; only
potential interactions (orange flag) and serious interactions (red flag)
were included.

Polypharmacy was defined as 5 or more concomitant drugs excluding ART.

\emph{Statistical analysis}

Quantitative variables were expressed as mean, SD, and range;
qualitative variables were expressed as frequencies and percentages.
Discrepancies between prescription criteria were assessed using
crosstabs and compared using the Chi-square~test or Fisher exact test,
p-values~of~5\% or lower were considered to be~statistically
significant. The statistical analysis was performed using SPSS 15.0
(SPSS, Inc., Chicago, Illinois, USA).

\textbf{RESULTS}

The study population comprised 91 patients aged [?]65 years from the
Over50 cohort. The mean (SD) age was 72.1 (5.6) years, and 74 patients
were men (81.3\%). Sixty-nine patients (75.8\%) had [?]3 comorbidities,
and polypharmacy was recorded in 54 patients (59.3\%).

The characteristics of the patients are presented in table 1.

\emph{Prescribing issues}

Prescribing issues (at least 1 PIM/PIP, PPO, and/or drug-drug
interaction) based on any criteria were identified in 80 patients
(87.9\%).

According to the STOPP/START criteria, we observed the following: 65
patients (71.4\%) had inappropriate prescriptions, with a mean (SD
{[}range{]}) of 1.27 (1.18 {[}0.00-6.00{]}) per subject; 45 patients
(49.5\%) were taking at least 1 concomitant medication that had to be
stopped (PIP) (0.69 {[}0.85, 0.00-4.00{]} per patient); and 39 patients
(42.9\%) should have been receiving 1 concomitant medication that they
were not receiving (PPO) (0.58 {[}0.79, 0.00-4.00{]} per patient).

According to the Beers criteria, 41 patients (45.1\%) had at least 1 PIM
(0.78 {[}1.10, 0.00-5.00{]} per patient). The results are shown in
figure 1.

When both sets of criteria were compared, 56.9\% of the cases in which a
prescription issue was detected by the STOPP/START criteria were also
detected by the Beers criteria, while 92.5\% of the cases in which a
prescription issue was detected based on the Beers criteria were
detected by the STOPP/START criteria (p\textless{}0.001).

A total of 83 potentially relevant drug interactions (orange/red flags)
were found between ART and concomitant treatment in 41 patients
(45.1\%), with a mean (SD {[}range{]}) of 0.93 (1.36 {[}0.00-6.00{]});
of these, 3 were severe (red) in 2 patients (2.2\%).

\emph{Drugs and drug families associated with prescribing issues}

The drug families associated with prescribing issues according to the
STOPP/START and the Beers criteria are described in detail in tables 2
and 3, respectively.

Briefly, when both sets of criteria were taken into account,
benzodiazepines were the family that most frequently had to be
discontinued; based on the STOPP criteria, benzodiazepines were followed
by opioids and anticholinergic agents; according to the Beers criteria,
vasodilators, selective serotonin reuptake inhibitors (SSRIs), and
non--cyclooxygenase-selective nonsteroidal anti-inflammatory drugs
(NSAIDs) were the categories that had to be stopped.

The most frequent drugs that should have been started (PPO) were the
seasonal trivalent influenza and the pneumococcal vaccines, as well as
vitamin D and calcium supplements.

The most frequent drug involved with potentially relevant interactions
was cobicistat in 20 patients (22.0\%), followed by dolutegravir in 9
(9.9\%), metformin in 8 (8.8\%), and mirenal supplements in 5 (5.5\%).

The 3 most severe interactions, which affected 2 patients, were
elvitegravir/cobicistat with clopidogrel and darunavir/cobicistat with
carbamazepine and fluticasone.

\textbf{DISCUSSION}

The prevalence of prescribing issues---PIMs/PIP, PPOs, and drug
interactions---reached almost 90\% and is a cause for concern among
older HIV-infected patients. We identified several differences according
to the criteria applied to identify these issues.

Older PLWH are often affected by comorbidities and polypharmacy
{[}24-26{]} and can therefore be considered an at-risk population for
prescribing issues and, consequently, for ADRs. However, to our
knowledge, only 3 published studies have assessed this issue in PLWH
{[}27-29{]}. Our results from the Over50 cohort show that almost all of
the patients aged [?]65 years presented at least 1 prescribing issue; half
had received at least 1 medication that had to be stopped (PIM by Beers
or PIP by STOP). This high rate is similar to that detected in San
Francisco in the USA {[}27,28{]}. One study detected at least 1 PIM in
52\% of patients in a group of 89 PLWH based on the Beers criteria
{[}27{]}. A similar prevalence was seen in a second study {[}28{]},
which included a larger sample (211 patients) and compared both the
STOPP/START and the Beers criteria, as did we. Of note, prescribing
issues were more prevalent when the Beers criteria were applied than
when the STOPP criteria were applied (63\% vs 54\%, respectively). Since
the population studied was American, this result was expected. Data from
the Swiss cohort {[}29{]} show that the prevalence of PIMs in 122
patients aged \emph{\textgreater{}} 65 years based only on the Beer
criteria was lower than that observed among our patients based on the
Beers and the STOPP criteria, around one third of the population
compared with a half, respectively. More than half of the medications
for which the Beers criteria apply are not available in Spain, and this
could be one of the reasons why prescribing issues in Europe are more
frequently detected with the STOPP criteria than with the Beers criteria
{[}12{]}. In this sense, these data indicate that the STOPP/START
criteria are more appropriate than the Beers criteria for evaluation of
prescribing issues in a European population.

Benzodiazepines were the drugs most frequently involved with PIMs in our
and the Swiss cohort {[}29{]}. These medications are widely prescribed
to the patients we attend, and those with long-term effects should be
avoided in elderly patients at risk of falls and in those receiving
other drugs that act on the central nervous system. In the American
population, however, testosterone was the most frequently involved drug,
probably owing to more frequent prescription of this drug among older
American PLWH. In contrast, vaccines and vitamin D supplements were the
recommended drugs least often prescribed. In line with national
guidelines, it is also necessary to recommend vaccines and vitamin D
supplements among older PLWH. Therefore, it is very important to
carefully and regularly check the concomitant treatment of elderly PLWH
at each medical visit, especially in cases involving multiple
comorbidities and polypharmacy where different prescribers are involved
{[}29-31{]}. This routine avoids unnecessary medications, adverse
events, and drug-drug interactions.

Finally, our results also illustrate the relevance of choosing the most
appropriate antiretroviral drug in elderly PLWH. As expected,
antiretroviral combinations including the booster cobicistat were more
frequently associated with drug-drug interactions. For that reason,
these combinations should be proactively monitored. Recent studies
support the antiviral efficacy and safety profile of ART combinations
without a booster and some dual regimens {[}32-35{]} in order to
decrease the risk of drug-drug interactions associated with boosters and
prescription errors, as well as the risk of ADRs. In fact, despite the
lack of formal recommendations on optimal therapy for older PLWH, cohort
data demonstrate that the presence of comorbidities and polypharmacy led
the physician to prescribe unusual ART combinations, mostly dual
regimens {[}36{]}.

Our study is potentially limited by its small sample size and by the use
of the previous version of the Beers criteria (although the
modifications of the 2015 revision made little difference to our
results) {[}37{]} . However, the data resulting from our analysis are
solid and relevant and add to the scarce published data. In addition,
they highlight the need for changes in our routine practice.

In summary, prescribing issues were very prevalent among our older PLWH,
with the most frequent being PIMs/PIP that could lead to avoidable ADRs.
This high prevalence requires us to optimize treatment strategies by
implementing a multidisciplinary critical review of our treatment plan
as part of routine practice {[}30,38{]}. Concomitant medications should
be more carefully and regularly monitored, especially in patients with
multiple comorbidities and polypharmacy. Boosted antiretroviral
combinations in particular should be used with caution. Although no
standardized guidelines are available for PLWH, we consider the
STOPP/START criteria to be a useful tool for European populations, since
they seem to better detect prescribing issues, as they do in the general
population.

\textbf{CONFLICTS OF INTEREST AND SOURCE OF FUNDING}

\subsubsection*{This study was conducted as part of our routine
work.}

{\label{this-study-was-conducted-as-part-of-our-routine-work.}}

All the authors: none to declare any competing financial or
non-financial interests in relation to the work described.

\subsection*{ACKNOWLEDGEMENTS AND AUTHOR CONTRIBUTIONS
STATEMENT}

{\label{acknowledgements-and-author-contributions-statement}}

Special acknowledgments for Thomas O'Boyle for the test revision.

C.L, J.M., N.P., J.P, P.E, A.B, C.F., B.L., C.E., B.C. and E.N. visited
and compiled patient information.

N.P did the statistical analysis.

C.L., J.M. and E.N. wrote the main manuscript text and prepared figures.

All authors reviewed the manuscript.

\textbf{FIGURE LEGENDS}

Figure 1. Prescribing issues

\textbf{DATA AVAILABILITY STATEMENT}

The data that supports the findings of this study are available in the
supplementary material of this article (Tables).

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  Livio F,~Marzolini C. Prescribing issues in older adults living with
  HIV: thinking beyond drug--drug interactions with antiretroviral
  drugs. 2019; 10: 2042098619880122.
\end{enumerate}

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