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\begin{document}

\title{Anastrozole as a therapeutic option for gynecomastia in a person
receiving antiretroviral treatment: case report}



\author[1]{Elizabeth Senkoro}%
\author[1]{Maithili  Varadarajan}%
\author[1]{Caterina Candela}%
\author[1]{Christina  Antoniad}%
\author[1]{Marta Boffito}%
\affil[1]{Chelsea and Westminster Hospital}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
A middle-aged Caucasian man presented with a six-month history of
bilateral enlargement of the breasts associated with pain. His hormonal
profile was normal and no other underlying cause was identified, we
diagnosed him with idiopathic gynecomastia. He is living with HIV,
clinically stable (viral load \textless{}20copies/mL) and on injectable
antiretrovirals cabotegravir/rilpivirine. Tamoxifen is an anti-estrogen
recommended for gynecomastia and has been described in persons living
with HIV. In this case, tamoxifen could potentially induce the activity
of cytochrome P450 3A4 (CYP3A4), reducing rilpivirine concentrations,
which consequently may cause virological failure. According to the
National Health Service (NHS) guidelines in the UK, an aromatase
inhibitor can be used in place of tamoxifen. To date, there have been no
reported cases of using anastrozole as a treatment for gynecomastia in
people living with HIV, or of its co-administration with
antiretrovirals.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Gynecomastia is caused by an imbalance in oestrogen and testosterone
levels, which results in a high oestrogen to testosterone ratio. It can
occur physiologically during the neonatal period, puberty, and in older
men above 50 years (prevalence 36\% to 57\%), as well as in pathological
circumstances(1). In HIV, the prevalence of gynaecomastia ranges from
1.8\% to 3\% and is associated with androgen deficiency or the use of
some antiretroviral drugs, including efavirenz, stavudine and
didanosine(2,3).

Tamoxifen is a selective estrogen receptor modulator and has
traditionally been the go-to therapeutic option for managing
gynecomastia(4,5). In this case, tamoxifen could potentially induce the
activity of cytochrome P450 3A4 (CYP3A4), reducing rilpivirine
concentrations, which may cause virological failure(6). According to the
national health service (NHS) guidelines in the UK, an aromatase
inhibitor can be used in place of tamoxifen(7). To our knowledge, this
is a first case report highlighting anastrozole as a therapeutic option
for gynecomastia in a patient on a non-nucleoside reverse transcriptase
inhibitors (NNRTI) accounting for potential drug drug interaction
(DDIs).

\textbf{CASE}

A 56 year old man presented at the routine HIV outpatient clinic with
complaints of left and right breast discomfort for about six months
followed by gradual swelling of the left breast. He did not report any
change in body hair, libido or erectile dysfunction. Discomfort was
described as pins and needles, no itchiness, no discharge from the
nipples or skin changes were reported. He had no previous breast
problems, but his mother had a history of breast cancer.

He was known to the HIV service and had been living with HIV since 2001.
Previous antiretroviral treatment combinations include: stavudine +
lamivudine + efavirenz and zidovudine + lamivudine + efavirenz. Due to
progressive multifocal leukoencephalopathy, he was kept on zidovudine +
lamivudine + nevirapine + abacavir. In 2010, he transferred to our care
and was prescribed tenofovir + emtricitabine + nevirapine until 2017
when his treatment was changed to include an integrase inhibitor,
raltegravir (RAL) alongside tenofovir + emtricitabine. However, due to
intolerance to RAL, he was switched back to tenofovir + emtricitabine +
nevirapine in 2018. In June 2022, he opted for the injectable
combination of cabotegravir/rilpivirine to allieviate the anxiety around
daily HIV medication intake. He showed adherence to injection
appointments and remained virologically suppressed.

His current co-morbidities included well controlled hypertension,
hyperlipidaemia, non-obstructing calculi of the right kidney, benign
prostate hyperplasia and a recurring reducible left inguinal hernia. His
previous co-morbidities were left hernia repair, progressive multifocal
leukoencephalopathy with peripheral neuropathy, hypogonadism and
hypothyroidism. His current co-medications were atorvastatin,
solifenacin, ramipril, tadafil, multivitamins and probiotics. He is a
non-smoker and drinks alcohol occasionally. He works as a personal
trainer and is usually very active with no history of anabolic steroid
use.

On physical examination, he appeared well. His body mass index was 27.35
kg/m2, blood pressure 144/91mmHg and other vital signs were in normal
range. He had bilateral, sub-areolar, concentric breast masses, with
palpable nodules that were soft and mobile. There was tenderness on
palpation with no nipple discharge or axilla lymphadenopathy. His
hormonal blood workup was within normal range, . We suspected him to
have idiopathic gynecomastia and we referred him to the breast clinic
for further evaluations as well as to rule out pseudo-gynecomastia and
breast cancer.

\textbf{INVESTIGATIONS}

At presentation (06/04/2023) his laboratory work up comprised general
haematology, biochemistry and endocrinology panels (thyroid stimulating
hormone, free testosterone, cortisol, luteinising hormone, estradiol,
progesterone, sex hormone binding globulin, testosterone,
follicle-stimulating hormone levels and cancer antigen 15-3 level) were
all within the normal range with exception of a low estimated GFR CKD
EPI (glomerular filtration rate chronic kidney disease epidemiology
collaboration) 72ml/min/1.73m\textsuperscript{2} with a normal range
serum creatinine. One week later (on 13/04/2023), he was booked into the
breast clinic for further evaluations. An ultrasound scan was performed
by a consultant radiologist and it showed a large amount of glandular
looking breast tissue, with no signs of malignancy on the left side. On
the right side, there was no convincing glandular breast tissue and no
signs of malignancy either. A mammogram was also performed and showed a
small amount of glandular looking tissue slightly more on the left side
than the right side with no signs of malignancy on both sides. This
appearance is consistent with bilateral asymmetrical true gynecomastia.
His follow up biochemistry laboratory tests at the great clinic were
also within normal range, with exception of a low Estimated GFR CKD EPI
80ml/min/1.73m\textsuperscript{2} (normal range serum creatinine). And a
month later (05/05/2023), a control of his endocrinology panel was
repeated and results were still within normal range. A testicular
sonogram was performed and revealed a reducible left inguinal hernia
containing peritoneal content. His last (26/06/2023) biochemistry work
up remains within normal range.

\textbf{TREATMENT}

Based on clinical history, laboratory and radiological findings, he was
diagnosed with true gynecomastia. The patient was discussed at the HIV
service's multidisciplinary clinic and anastrozole was proposed as an
alternative to tamoxifen to avoid the possible drug-drug interaction
with rilpivirine. He was started an oral dose of anastrozole 1 mg once
daily. After 10 days from the start of anastrozole, he presented a
significant symptom improvement with visible reduction of breast
enlargement and decreased discomfort. After six weeks of use of
anastrozole, complete resolution of the gynecomastia occurred and the
patient stopped anastrozole.

In the meantime (19/05/2023), the patient referred weight gain of 3
kilograms (in a span of 11months) and opted for switching back to oral
antiretroviral treatment containing tenofovir + lamivudine + doravirine,
while he was still on anastrazole. The latter provided a benefit (versus
the most commonly used tamoxifen) with this ARV combination as well, as
a drug-drug interaction between tamoxifen and doravirine, although not
studied, may occur and again lead to a decrease in doravirine
concentrations through CYP3A4 induction\textsuperscript{9}.

\textbf{OUTCOME AND FOLLOW UP}

After 10 days of treatment, the patient's breast enlargement reduced,
but moderate fatigue was experienced. He mentioned taking more frequent
naps, having low energy, and lacking motivation for the gym. Examination
showed mild tenderness in the peri-areolar area and reduced breast
tissue. The patient was advised to continue anastrozole and injectable
ARVs. However, due to weight gain concerns, he expressed interest in
switching to ARV tablets. After reassurance, he was scheduled to switch
next month. At week 4 follow-up, the patient tolerated anastrozole well
despite fatigue. He switched to TDF/FTC/doravirine tablets at week 6,
reporting complete resolution of breast enlargement and tenderness.

\textbf{DISCUSSION}

Antiretrovirals are essential lifelong medications for managing HIV, and
it's crucial to understand the associated drug interactions (DDIs) to
improve treatment outcomes and safety. Injectable antiretrovirals can
reduce DDI risks by avoiding the gastrointestinal route, but caution is
necessary for those metabolized by CYP3A4 in the liver(8). In our case,
the patient is on injectable antiretroviral therapy containing
rilpivirine and also requires medical treatment for gynecomastia.
Combining drugs that induce CYP3A4 activity with antiretrovirals
primarily metabolized by CYP3A4 (such as protease inhibitors (PIs) or
NNRTIs like rilpivirine) can decrease their levels, potentially leading
to viral failure or drug resistance.

Treatment options for gynecomastia include: reassurance or observation,
discontinuation of the causative agents and addressing underlying
disease. Medical therapies include: estrogen antagonists as first line
and alternatively a weak androgen or an aromatase inhibitor(4,5,7).
Although tamoxifen is not licensed for treatment of gynecomastia, it is
widely used and recommended by several guidelines with reports of good
response\textsuperscript{1}. It's use in gynecomastia among the general
population and people living with HIV has been described
previously(9,10). Tamoxifen is an estrogen antagonist and undergoes wide
hepatic metabolism involving some isoforms of the cytochromes. It
induces the activity of CYP3A4 both in vivo and in vitro(6). According
to the HIV liverpool drug-drug interaction checker, when tamoxifen is
taken with rilpivirine, this induction may lead to a decrease in the
exposure of rilpivirine as well as other antiretrovirals primarily
metabolized by CYP3A4.

The European Academy of Andrology (EAA) guidelines discourage the use of
selective estrogen receptor modulators, aromatase inhibitors and
dihydrotestosterone due to lack of quality data(4). However, the
association of breast surgery and Nottinghamshire Area Prescribing
Committee (APC) NHS permits the use of aromatase inhibitors
(anastrozole) if tamoxifen is not well-tolerated or as a secondary
option if anastrozole shows no response(7,11). Anastrozole is a
selective non-steroidal aromatase inhibitor that hinders the activity of
the enzyme CYP19A1 (aromatase), responsible for converting androgens
into estrogens(12). It has been used in chemoprevention and adjuvant
therapy for post-menopausal women at risk of breast cancer(13,14), with
notable side effects like osteoporosis, nausea, and hot flashes(13--15)
and for gynecomastia in adolescents(16,17). Despite the lack of
available studies on the co-administration of anastrozole with most
antiretroviral agents, the likelihood of a clinically significant
interaction is low. This is primarily attributed to anastrozole's
inhibitory nature, which reduces the potential for diminishing the
concentration of antiretroviral drugs(6).

Our case report offers a contribution on treatment of gynecomastia using
anastrozole and explains the possible interactions with antiretrovirals.
The increasing use of injectable antiretroviral therapy in the near
future leads us to find an alternative to tamoxifen to avoid drug drug
interactions with rilpivirine or other antiretroviral therapy as well as
other antiretrovirals majorly metabolized by CYP3A4.

\textbf{CONCLUSION}

Tamoxifen potentially interacts with NNRTIs like rilpivirine and
doravirine reducing their concentrations. This case report suggests that
anastrozole may be used instead of tamoxifen for the treatment of
gynecomastia in men living with HIV who are taking NNRTIs or PIs.
Aromatase inhibitors may be considered for use for gynecomastia
management, to avoid drug-drug interactions but further studies are
needed to confirm these findings.

\textbf{CONTRIBUTORS}

ES, CC and MV contributed to manuscript writing and care of the patient.
CA is the nurse responsible for direct care of the patient. MB is the
responsible consultant for the care of the patient and was responsible
for the revision of the manuscript.

\textbf{COMPETING INTERESTS}

The authors have no competing interests and no financial support to
disclose.

\textbf{INFORMED CONSENT}

Written informed consent was obtained from the patient for publication
of this case report

\textbf{REFERENCES}

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treatment. Endotext {[}Internet{]}. 2023;

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3. Biglia A, Blanco JL, Martínez E, Domingo P, Casamitjana R, Sambeat M,
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5. Catherine B. Niewoehner, Dennis Styne, Harold Carlson and GB.
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