Page 329 - SAHCS HIVMed Journal Vol 20 No 1 2019

Page 5 of 7 Original Research

TABLE 4: Antiretroviral therapy exposure and adverse events for abnormal Firstly, immune reconstitution inflammatory syndrome
breast (n = 41). (IRIS) has been described as a possible mechanism through
Characteristic Variable N %
EFV exposure Accumulative time on 5.5 years 3.8–8.5 the production of cytokines which increase breast tissue
n = 37 (100%) EFV-based regimen†,‡ aromatase activity causing increased oestrogen production.
4
D4T exposure Accumulative time on D4T 4.9 years 1.8–7.2
n = 22 (59.5%) based regimen‡,§ This was an unlikely cause in our cohort, as IRIS usually
13
Lipodystrophy syndrome Total 19 46.3 takes place within 6 months of starting ART, and most
Lipoatrophy 6 14.6 adolescents with abnormal breasts had received ART for a
Fat accumulation 9 22.0 median time of 5 years, with the median duration of their
No description 4 9.8
Investigations Total 3 7.3 current ART regimen being 2 years.
Sonography 1 2.4
Blood tests 2 4.8 Secondly, abnormal breast development in adults is frequently
Prescribed interventions Total 21 51.2 attributed to lipodystrophy syndrome. Lipodystrophy,
14
EFV substitution 13 31.7 defined as the presence of lipoatrophy and/or lipohypertrophy,
Other ART change 3 7.3
EFV and other substitution 3 7.3 was by far the most common comorbidity seen in patients in
Diet and exercise 1 2.4 this cohort, with nearly half of those with abnormal breasts
Tamoxifen prescribed¶ 1 2.4 reported to have lipodystrophy. Lipodystrophy is associated
ART, Antiretroviral therapy; EFV, efavirenz. with receiving D4T and zidovudine. Despite very few
14
†, Measured up until first breast abnormality/change from EFV. patients with breast abnormalities receiving D4T at the time of
‡, Median (IQR).
§, Measured up until change from stavudine (D4T). censure (n = 10), D4T was found to be associated with the
¶, Tamoxifen prescribed but not received (taken from the clinical notes). development of abnormal breasts (p = 0.028). The mechanism
is most likely through altered fat accumulation as part of
Discussion lipodystrophy.

This study aimed to determine whether ART drugs, especially
EFV, were associated with breast abnormalities in adolescents. Thirdly, hypogonadism, which is a mechanism thought to
We found that the prevalence of breast abnormalities in this cause gynaecomastia in adult male patients on ART, was not
15
cohort of HIV-infected adolescents on ART was 5.9% and that explored as a cause in this cohort; however, the imbalance
breast abnormalities in adolescents on ART were associated between oestrogen and androgens during adolescence may
with current EFV use (p = 0.016) and older age in adolescence play a role in adolescent boys. 3
(p < 0.0005).
Lastly, oestrogen receptor activation by ARV drugs, particularly
With such large populations of adolescents on ART in South EFV, is a likely cause in this cohort. At the time of reporting
5,16
Africa, common side effects, such as breast abnormalities of an abnormal breast event, receiving EFV was significantly
experienced in a specific age group, become evident. A associated with the development of breast abnormalities.
significant difference in age was observed and adolescents Furthermore, all patients with abnormal breast conditions had
with breast abnormalities were older, and thus on ART for
longer, than those without breast conditions. Most received EFV as part of a previous regimen and their exposure
abnormalities of the breast in this cohort were experienced at was often long-term with the mean time of exposure being 5.5
a median age of 15.5 years, which is somewhat later than years. Efavirenz use was associated with the development of
physiological gynaecomastia in boys, peaking earlier abnormal breast conditions in this adolescent population
between the ages of 13 and 14 years. 3 which is supported by other adolescent and adult studies with
similar outcomes. 1,5,6,16
Despite there being more girls in the cohort, there were
significantly more breast events seen in male patients. Breast Breast abnormalities
abnormalities in males are easier to detect and define because
of the ‘all or nothing’ nature of the abnormalities. Nearly half of the cases of breast abnormality were described
as enlargement and just less than half were described using
The link between ART drugs and breast abnormalities has the terms ‘gynaecomastia’ and ‘lipomastia’, which appear to
not been well established. In this cohort, most patients were be used interchangeably. The prevalence of severe breast
receiving EFV in combination with abcacavir (ABC) and 3TC abnormalities for the whole population was 0.5%, which was
(65.2% of the cohort). From this regimen, only EFV was the same as the prevalence reported in the Collaborative HIV
shown to be associated with abnormal breast development. Paediatric Study. 1
This suggests that in most patients with breast abnormalities
who were receiving ABC/3TC/EFV, EFV remains the likely Obtaining a definitive diagnosis of gynaecomastia or breast
candidate.
enlargement remains a challenge because of the lack of
available diagnostic modalities and expertise. Sonography is
Theories about abnormal breast development suggested to differentiate between lipomastia related to
At present, there are four plausible mechanisms by which lipodystrophy and true gynaecomastia; however, in practice,
ARV drugs or HIV itself can cause breast abnormalities. this is not definitive. 4

http://www.sajhivmed.org.za 322 Open Access