Severe Lipodystrophy and Gynecomastia in a Male Patient on Lopinavir Based Second-Line Antiretroviral Therapy

Abstract

With the introduction of highly active antiretroviral therapy,
there has been a dramatic improvement in the clinical course
of patients with human immunodeficiency virus infection
and acquired immune deficiency syndrome. However,
the favorable virological, immunological, and clinical profile
of highly active antiretroviral therapy comes at the cost of
some common and, at times, severe metabolic adverse effects
such as dyslipidemia, body fat dysregulation/lipodystrophy,
insulin resistance, and diabetes mellitus. We
describe a case of a male patient from North India who developed
similar adverse effects including gynecomastia
while on the protease inhibitor lopinavir; the mention of
such case is rare in the existing literature.

Full text

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Address for Correspondence: Alpesh Goyal, Department of Endocrinology and Metabolism, AIIMS, New Delhi
Phone: 91-9818154876 E-mail: alpeshgoyal89@gmail.com Received: 17/01/2017 Accepted: 05/06/2017
®Copyright 2018 by Turkish Journal of Endocrinology and Metabolism Association
Turkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri
Severe Lipodystrophy and Gynecomastia
in a Male Patient on Lopinavir-based
Second-line Antiretroviral Therapy
Şiddetli Lipodistrofi ve Jinekomastisi Olan Erkek Hastada
Lopinavir Tabanlı İkinci Basamak Antiretroviral Tedavi
AIIMS, Department of Endocrinology and Metabolism, New Delhi
*AIIMS, Department of Internal Medicine, New Delhi
Case Report
Turk J Endocrinol Metab 2018;22:208-212
Introduction
Since the beginning of the human immunodefi-
ciency virus infection-acquired immune defi-
ciency syndrome (HIV-AIDS) epidemic in the
year 1980, more than 75 million people have
been infected with HIV and more than 36 mil-
lion have died of this dreaded disease. Although
progress has been made on HIV-AIDS treat-
ment, the global crisis of HIV-AIDS shows few
signs of slowing down. The introduction of highly
active antiretroviral therapy (HAART) has
changed the natural history of the disease and
led to a substantial decline in infection-related
morbidity and mortality. However, these bene-
fits come at the cost of significant toxicity on a
long-term exposure, including metabolic ad-
verse effects such as dyslipidemia, lipodystro-
phy, insulin resistance, hepatic steatosis,
diabetes mellitus, increased cardiovascular risk,
and lactic acidosis. Initially, the development of
these effects was ascribed solely to protease in-
hibitor (PI) therapy, but it was later found to be
related to certain nucleoside reverse transcrip-
tase inhibitors as well. Lipodystrophy, or fat re-
distribution syndrome, is a term used to
characterize the various changes in body fat
composition. Various mechanisms for lipodys-
trophy in HIV have been suggested, including
DOI: 10.25179/tjem.2017-56570
With the introduction of highly active antiretroviral therapy,
there has been a dramatic improvement in the clinical co-
urse of patients with human immunodeficiency virus infec-
tion and acquired immune deficiency syndrome. However,
the favorable virological, immunological, and clinical profile
of highly active antiretroviral therapy comes at the cost of
some common and, at times, severe metabolic adverse ef-
fects such as dyslipidemia, body fat dysregulation/lipodys-
trophy, insulin resistance, and diabetes mellitus. We
describe a case of a male patient from North India who de-
veloped similar adverse effects including gynecomastia
while on the protease inhibitor lopinavir; the mention of
such case is rare in the existing literature.
Keywords: HIV-AIDS; HAART; dyslipidemia;
metabolic syndrome; lipodystrophy;
insulin resistance; gynecomastia
Yüksek etkinlikli antiretroviral tedavinin kullanıma girme-
siyle birlikte insan immün yetmezlik virüs enfeksiyonu ve
kazanılmış immün yetmezlik sendromu olan hastaların kli-
nik seyirlerinde dramatik bir iyileşme olmuştur. Ancak,
Yüksek etkinlikli antiretroviral tedavinin olumlu virolojik,
immünolojik ve klinik profiline karşılık sık rastlanan ve
kimi zaman da şiddetli olabilen dislipidemi, vücut yağ dis-
regülasyonu/lipodistrofi, insülin direnci ve diabetes melli-
tus gibi bazı metabolik yan etkiler ortaya çıkmaktadır. Bu
çalışmada, bir proteaz inhibitörü olan lopinavir ile tedavi
edilmekte iken, jinekomasti de dâhil benzer advers etkiler
gözlediğimiz kuzey Hindistanlı bir erkek hasta, güncel li-
teratürde az rastlanmasından dolayı sunulmuştur.
Anahtar kelimeler: HIV-AIDS; YEART; dislipidemi;
metabolik sendrom; lipodistrofi;
insülin direnci; jinekomasti

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Turk J Endocrinol Metab Goyal et al.
2018;22:208-212 Lopinavir ART and Gynecomastia/Lipodystrophy 209
chronic HIV infection itself, mitochondrial dysfunction,
cytokine alterations, direct toxicity of PIs, and other an-
tiretroviral use.
Case Report
A 41-year-old male patient was detected with HIV infec-
tion in January 2004 and was initiated on antiretroviral
therapy (ART) since then. He has been under follow-up in
the Infectious Disease Clinic at our hospital, and the
treatment details are outlined in Table 1.
On an outpatient visit in 2014, the patient reported con-
cerns regarding symptoms of progressive weight gain,
abnormal body fat distribution in the form of central obe-
sity, and prominent fat deposit at the back of the neck.
He denied noticing any purple striae, easy bruising, prox-
imal weakness, or hyperpigmentation. There was an as-
sociated history of gradually progressive nonpainful
breast enlargement bilaterally for last 4-5 years. He de-
nied the history of erectile dysfunction or decreased fa-
cial hair shaving frequency. The patient did not have any
addictions in the form of smoking/alcohol/recreational
drug use. There was no history to suggest exogenous
steroid exposure. However, he had a sedentary lifestyle
with irregular and malicious dietary habits. He was also
detected to have hypertension and diabetes mellitus
4 years back for which treatment was ongoing with oral
antihyperglycemic drugs (OADs) and antihypertensives.
Clinical examination revealed a middle-aged male patient
with the following anthropometric parameters: weight:
100.5 kg, height: 172 cm, body mass index: 33.9 kg/m2,
waist circumference: 104 cm, hip circumference: 116
cm, waist-to-hip ratio: 0.896, blood pressure:
142/90 mmHg (right arm, supine position). Grade 4
acanthosis nigricans was noted over the neck. Lipohy-
pertrophy in the form of supraclavicular fat accumulation
and a dorsocervical fat pad (buffalo hump) were also
seen. Goiter, skin tags, abdominal striae, ecchymosis,
and proximal weakness were absent and hyperpigmen-
tation was present in the areas of acanthosis. Bilateral
nontender gynecomastia (with glandular diameter >4 cm
on both sides) was also noted. Bilateral testes were nor-
mally palpable in the scrotum (volume: 20 mL bilaterally
by Prader orchidometer). Systemic examination was es-
sentially normal (Figure 1).
Investigative work-up including blood counts, elec-
trolytes, and liver and renal function tests was unre-
markable. Fasting venous plasma glucose was 160 mg%
with glycated hemoglobin of 7.8%. Fasting lipid profile
(after 8 hours of overnight fasting) was deranged with
total cholesterol (211 mg%), triglycerides (281 mg%),
low-density lipoprotein (LDL) cholesterol (140 mg%) and
high-density lipoprotein (HDL) cholesterol (29 mg%).
Hormonal investigations including serum T4 (8.4 µg/dL;
range: 5.1–14.1 µg/dL), serum thyroid-stimulating hor-
Month/Year ART Drugs CD4 Cell Count (/µL) Comments
Jan 2004-August 2006 Stavudine, Lamivudine, Nevirapine 326-March 2005 Poor compliance with treatment reported.
262-February 2006
August 2006-January 2007 Stavudine, Lamivudine, Efavirenz 180-August 2006 Patient started on antitubercular therapy for tubercular lymphadenitis.
57-December 2006 Nevirapine substituted for Efavirenz.
January2007-March 2007 Stavudine, Lamivudine, Nevirapine 20-January 2007 Nevirapine substituted for Efavirenz after completion of ATT.
35-March 2007 Drug failure suspected due to persistent CD4 decline.
HIV viral load at this time was high (1.8×105 copies/mL)
Decision to switch over to PI (Protease Inhibitor) based regimen made.
March 2007 till date Tenofovir, Emtricitabine, Lopinavir/Ritonavir 414-October 2007 Immunological and clinical recovery occurred with second line regimen.
685-July 2013 Patient developed lipodystrophy, dyslipidemia, diabetes, hypertension.
Table 1. Details of antiretroviral treatment received by the patient.

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210
mone (2.47 mIU/mL; range: 0.27-4.2 mIU/mL),
serum luteinizing hormone (LH) (3.5 mIU/mL;
range: 1.7-8.6 mIU/mL), serum follicle-stimulat-
ing hormone (FSH) (7.4 mIU/mL; range: 1.5-
12.4 mIU/mL), serum testosterone (3.7 ng/mL;
range: 2.4-8.3 ng/mL), and serum morning cor-
tisol (15.6 µg/dL; range 6.2-19.4 µg/dL) were
within normal limits.
He was prescribed dietary and lifestyle modifica-
tions in form of 1400-kcal diet and was advised
regular aerobic exercise. For dyslipidemia, lipid-
lowering therapy with rosuvastatin 10 mg was
added. The patient was advised to continue sim-
ilar OADs and ART regimen.
Discussion
Lipodystrophy, or fat redistribution syndrome, is
a term used to characterize the various changes
in body fat composition. It may be classified as
lipohypertrophy, lipoatrophy, or mixed form. Var-
ious mechanisms for lipodystrophy in HIV have
been suggested, including chronic HIV infection
itself, hypercortisolism and steroid perturbations,
mitochondrial dysfunction, cytokine alterations,
direct toxicity of PIs, and other antiretroviral use
(1-4). Clinically, fat wasting has been described
as sunken eyes, sunken cheek, temple hollow-
ness, prominent zygomatic arch, prominent
veins, loss of skin folds, and loss of shape and
contour of buttocks. Fat hypertrophy is described
as facial fat accumulation, dorsocervical fat pad
(buffalo hump), breast enlargement, increase in
abdominal girth, and presence of lipomas. In
order to overcome these body changes, each
case must be treated on an individual basis as
data for the normality of body fat distribution do
not exist.
Male breast tissue development and maintenance
is mainly regulated by the local androgen:estro-
gen ratio. Gynecomastia, defined as a benign
proliferation of male breast glandular tissue, is
caused principally by an imbalance in the breast
androgen:estrogen ratio. Prolactin, growth hor-
mone, insulin, insulin-like growth factor 1, and
cortisol are permissive trophic factors that re-
quire an imbalance in estrogen and androgens to
cause gynecomastia.
Gynecomastia occurs physiologically in neonates,
pubertal boys, and adult men. However, males
with new onset of gynecomastia that is tender,
>4 cm, or with a progressive increase in size
should be evaluated. The etiological causes of
pathological gynecomastia can be divided into
the following categories:
a) Androgen deficiency states as primary and
secondary hypogonadism.
b) Conditions with resistance to testosterone ac-
tion as androgen insensitivity syndrome.
Figure 1: Image showing severe acanthosis nigricans and prominent dorsocervical fat pad and bilateral gynecomas-
tia in the patient.

c) Estrogen excess states as estrogen-secreting
testicular or adrenal neoplasms, familial aro-
matase excess syndrome.
d) Systemic diseases such as chronic liver dis-
ease, chronic kidney disease, HIV infection
e) Drug-induced gynecomastia due to the use of
estrogen, testosterone, human chorionic go-
nadotropin (HCG) preparations, spironolactone,
cimetidine, flutamide, bicalutamide, opioids,
marijuana, alcohol, and HAART
Many pathological states, such as thyrotoxicosis,
have multiple contributory factors to the causa-
tion and cannot be strictly categorized into one
broad mechanism. A detailed history and exami-
nation, including the examination of genitalia for
any ambiguity, testicular asymmetry, or mass le-
sion, is therefore needed in each patient with
pathological gynecomastia.
The minimum laboratory evaluation needed in a
patient includes liver and renal function tests, thy-
roid function tests and serum testosterone, FSH,
and LH evaluation. Additional evaluation is based
on the history, examination, and the results of ini-
tial tests. Prolactin is a permissive lactotrophic
hormone that stimulates breast growth when es-
trogen effects are relatively high compared with
testosterone effects, but prolactin alone is unlikely
to cause gynecomastia as men with hyperpro-
lactinemia lack this finding. By contrast, tumors
secreting estradiol, dehydroepiandrosterone sul-
fate, and HCG suppress gonadotropin (LH/FSH)
levels; therefore, these tests are only needed in
selected cases with suppressed gonadotropin lev-
els. In most cases with gynecomastia, a definitive
cause is not found; therefore, these cases are la-
beled as idiopathic gynecomastia.
In our patient, we suspected the possibility of HIV-
and HAART-induced gynecomastia; however, a
basic evaluation to rule out alternative causes was
performed, which was negative. Serum sex hor-
mone-binding globulin levels are increased in 30-
55% patients with HIV infection; hence, free
testosterone is a better marker to diagnose hy-
pogonadism in these patients. Free testosterone
testing could not be performed in our patient as
the test is unavailable at our center.
Per se, HIV infection is associated with an in-
creased prevalence of gynecomastia. Possible
contributing factors include hypogonadism, in-
creased use of illicit and prescription drugs
known to cause gynecomastia, and severe
chronic kidney or liver disease. Moreover, any
form of HAART regimen may be associated with
an increased risk of gynecomastia, but regimens
including efavirenz have reportedly been the
most likely reasons to cause gynecomastia.
Several studies have described breast enlarge-
ment in female patients taking protease inhibitors,
suggesting a similar possibility in males (5,6).
However, there are only very few reports describ-
ing male breast enlargement with PI-based ther-
apy. Donovan et al. (7) described four cases of
gynecomastia in a total of 500 men on PI-based
therapy (mostly saquinavir), of which gyneco-
mastia was reversed in three cases after discon-
tinuation of the drug. However, it may not be
appropriate to attribute gynecomastia entirely to
PI-based therapy as several other factors includ-
ing the use of nucleoside analogs, drug interac-
tions, and HIV infection itself may also contribute.
The etiopathogenesis of HAART-induced gyneco-
mastia is not clear, but a proposed hypothesis is
that HAART increases the local production of in-
terleukins that increase breast aromatase activ-
ity and/or directly stimulate breast growth (13).
Lipodystrophy can be assessed and monitored
using patient self-assessment, clinical examina-
tions, skinfold thickness measurement, and
imaging techniques (dual-energy X-ray absorp-
tiometry, magnetic resonance imaging, computed
tomography). The treatment options for lipodys-
trophy include switching over non-PI-based ther-
apy, which may not be feasible in all cases; use
of recombinant growth hormone, which may
place patients at increased risk for developing di-
abetes; use of lipid-lowering agents; use of an-
tidiabetic agents such as metformin (10) and
pioglitazone; and surgical treatments such as li-
posuction (11) and subcutaneous mastectomy.
Dyslipidemia has been described at a prevalence
of 20-80% in HIV-infected patients in various
studies. Several factors contributing to lipid ab-
normality in this population include HIV infection
itself; antiretroviral drugs, particularly PIs; ge-
netic factors; and conventional dietary and
lifestyle factors. HIV infection is associated with
an increase in triglycerides and decrease in HDL
cholesterol, LDL cholesterol, and total cholesterol
levels, while PI-based therapy leads to increase
in total cholesterol, triglycerides and LDL choles-
terol and a decrease in HDL cholesterol (1).
These abnormalities along with an increase in the
incidence of insulin resistance and glucose intol-
erance (8,9) in patients on PIs place them at risk
for the accelerated atherosclerotic disease.
Therefore, abnormalities must be sought for and
managed aggressively. Along with appropriate di-
etary and lifestyle management, lipid-lowering
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therapy goes a long way in managing this com-
plication.
Most of the hydroxymethylglutaryl-coenzyme A
reductase inhibitors (statins) are metabolized by
the cytochrome (CYP) P450 3A4 pathway, with
the exception of rosuvastatin, fluvastatin
(CYP2A9), and pravastatin (sulfation). There-
fore, caution must be taken while prescribing
these drugs with PIs, which are CYP3A4 in-
hibitors (12), as the accumulation of these drugs
can lead to various adverse effects such as he-
patotoxicity, myalgia, rhabdomyolysis, and
myositis.
Source of Finance: During this study, no finan-
cial or spiritual support was received neither from
any pharmaceutical company that has a direct
connection with the research subject, nor from a
company that provides or produces medical in-
struments and materials which may negatively
affect the evaluation process of this study.
Conflict of Interest: No conflicts of interest be-
tween the authors and/or family members of the
scientific and medical committee members or
members of the potential conflicts of interest,
counseling, expertise, working conditions, share
holding and similar situations in any firm.
Author Contributions
Concept: Alpesh Goyal; Design: Ashutosh Biswas;
Data Collection or Processing: Alpesh Goyal; Analy-
sis or Interpretation: Ashutosh Biswas; Literature
Search: Alpesh Goyal; Writing: Alpesh Goyal.
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