World Journal of AIDS, 2013, 3, 187-191 Published Online September 2013 ( 187
Graves’ Disease as a Late Manifestation of Immune
Reconstitution Syndrome after Highly Active
Antiretroviral Therapy in an HIV-1 Infected Patient
Evelin Mingote1, Agustina Urrutia1, Alejandra Viteri2, Cristina Faingold1, Carla Musso1
1Department of Endocrinology and Metabolism, Doctor César Milstein Hospital, Buenos Aires, Argentine; 2Department of Infectol-
ogy, Doctor César Milstein Hospital, Buenos Aires, Argentine.
Received February 21st, 2013; revised March 21st, 2013; accepted April 21st, 2013
Copyright © 2013 Evelin Mingote et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Context: Highly active antiretroviral therapy (HAART) inhibits the HIV replication and consequently increases CD4
levels and decreases viral load. This immune system improvement can trigger various immunological phenomena,
entity called Immune Reconstitution Syndrome (IRS). Graves’ disease is a late Immune Reconstitution consequence.
Patient: We report the case of a 48 years old man with HIV infection who developed Graves’ disease three years after
he was on effective HAART because of the Immune Reconstitution Syndrome. At presentation he had a very low CD4
T-cell count (17 cells/µL). When he started HAART h e presented a lipodystrophy syndrome. HAART was ch anged be-
cause of the persistent low CD4-T cells count (less than 100 cell/µL). Afterwards serum lipid levels began to decrease
and that was the first manifestation of Graves’ disease, which was diagnosed when CD4 T-cells increased up to 343
cell/µL. Our patient developed Graves’ disease 36 months after initiating effective HAART with protease inhibitors
which was coincident with viral suppression and a rise of CD4 T cells. Conclusion: The most immunosuppressed pa-
tients with a CD4 T cell count less than 100 cells/µL are at greatest risk for th e development of Immune Reconstitution
Syndrome after HAART initiation. We conclude that clinicians will have to consider the importance of the early diag-
nosis of thyroid disease to bring an adequate treatment.
Keywords: Graves’ Disease; Immune Reconstitution Syndrome; Highly Active Antiretroviral Therapy; HIV-1;
Lipodystrop hy Sy nd rome
1. Introduction
Highly active antiretroviral therapy (HAART) has been
shown to decrease progression and mortality rates of hu-
man immunodeficiency virus (HIV) infection, leading to
an increased incidence of metabolic abnormalities inclu-
ding insulin resistance, type 2 diabetes, hyperlipidaemia
and abnormal body fat redistribution known as lipodys-
trophy syndrome [1,2]. Antiretroviral drugs association
act by inhibiting the HIV replication and consequently
increased CD4 levels and decreased viral load (VL). This
immune system improvement can trigger various immu-
nological phenomena entity called Immune Reconstitu-
tion Syndrome (IRS) [3,4]. This syndrome can be ex-
presse d in weeks or years after startin g antiretrov iral the-
rapy and Graves’ disease (GD) is a late IRS consequence
2. Patient
The patient is a 48 years old man with HIV infection who
was diagnosed 7 years earlier. At presentation he had a
very low CD4 T-cell count of 17 cells/µL and a viral
load of 9100 copies/mL (Ta ble 1). His weight was 71 kg
and his height was 169 cm, normal body mass index and
normal blood pressure. Laboratory assay showed total
cholesterol (TC) 150 mg/dl, alkaline phosphatase 180 U/l
(0 - 240 U/l) and glucose 87 mg/dl. He was treated with
lamivudine, zidovudine (nucleoside reverse transcriptase
inhibitors, NRTI) and efavirenz (non-nucleoside reverse
transcriptase inhibitors, NNRTI). A few months later we
found an increase in TC (226 mg/dl) and a very high
triglycerides (TG) levels (793 mg/dl) associated with a
mild increase in CD4 T-cells count (41 cell/µL) and a
decrease in VL (less than 50 copies/mL). He began life-
Copyright © 2013 SciRes. WJA
Graves’ Disease as a Late Manifestation of Immune Reconstitution Syndrome
after Highly Active Antiretroviral Therapy in an HIV-1 Infected Patient
Table 1. Laboratory results during the clinical course.
Jan Oct Oct Oct 2009 Oct Jun Dec Normal
2005 2005 2006 2009 2010 2011 2011 Range
TC, mg/dl 150 226 205 63 198 123 191 <200
TG, mg/dl - 793 140 73 94 - 160 <150
Glu, mg/dl 87 - 110 112 93 107 103 70 - 110
CD4 (cells/µL) 17 41 96 343 411 406 416 600 -1200
VL (copies/m l) 9100 <50 <50 <50 <50 <50 <50 <50
TSH, µUI/ml - - - <0.03 <0.03 <0.03 1.37 0.3 - 5
FT4, ng/dl - - - 3.9 1.1 2 - 0. 9 - 1.9
ATPO (UI/ml) - - - 239 - - - <40
TSHRab% - - - 45 - - - <15
Jan 2005, HAART start; Oct 2005, lipodystrophy syndrome; Oct 2006, HAART change; Oct 200 9, Graves’ disease diagnosis; -, not done; Glu, glucose .
style modifications without response, followed by feno-
fibrate. One year after HAART was initiated, even
though he had TC and TG as expected, we observed a
loss of body fat on the face, chest and buttocks associated
with increased abdominal fat, gathering the lipodystro-
phy syndrome physical and metabolic characteristics as-
sociated with HAART. Because of the persistent CD4
T-cell count less than 100 cells/µL, HAART was chang-
ed to lopinavir and ritonavir (protease inhibitors, PIs) and
he continued with lamivudine and zidovudine. He deve-
loped without complications until three years. At that
moment, even though the immunological improvement
due to an in crease of CD4 T-cells until 343 cell/µL and a
decrease of VL less than 50 copies/ml, his TC was 63
mg/dl, HDL-c 32 mg/dl, LDL-c 16 mg/dl, TG 73 mg/dl,
alkaline phosphatase 387 U/l and an impaired glucose
tolerance. These values were associated with weight loss
and high blood pressure, initially interpreted as a pro-
bable HAART toxicity. The antiretroviral therapy was
changed to a new therapeutic with lower metabolic im-
pact, atazanavir (PIs), emtr icitabina , tenofovir (NRTI) and
fenofibrate was discontinued with extremely low persis-
tence of TC and LDL-c values. He had negative viral he-
patitis serologies and abdominal ultrasound without pa-
thological alterations. He then developed limb weakness,
insomnia, and weight loss. Physical examination reveal-
ed tremors, right exophthalmos, enlarged thyroid gland
and increase in heart rate. His thyroid-stimulating hor-
mone (TSH) was less than 0.03 mUI/ml, total thyroxine
(TT4) was 24 µg/d l (4.5 - 13 µg /dl), free th yroxine (FT4)
was 3.9 ng/dl, triiodo-thyronina (T3) was 7.2 µg/dl (0.8 -
1.9 µg/dl) and antithyroid antibodies (anti-thyroid per-
oxidase [anti-TPO] and thyrotropin receptor autoantibo-
dies [TSHRab]) were positive. It is important to note that
the first manifestation of GD in this patient was the
change of lipid parameters.
The patient was treated with propanolol 40 mg and
methimazole 40 mg. There was no past personal or fam-
ily history regarding thyroid disease. Two weeks later, he
had an improvement of his symptoms and lately he nor-
malized his blood pressure and lipid profile. The methi-
mazole dose was progressively decreased until a low
dose when he had clinical manifestation and biochemical
data of a hyperthyroidism again. Even though the anti-
thyroid dose was adjusted and his FT4 became normal in
a short period of time, his TSH remained suppressed up
to two years after he started antithyro id drugs.
3. Discussion
It is well known the association between HAART and
lipodystrofy syndrome with a prevalence greater than
50% and with dyslipidaemia, [6] leading to high levels of
TC, LDL-c and mainly TG [7]. Our patient developed
that syndrome and lately serum lipid levels began to de-
crease as a consequence of the GD initially unknown.
Since the change of lip id parameters were the oppo site of
what was expected in the lipodystrophy syndrome, di-
agnosis of GD should be taken into account as a dif-
ferential diagnosis.
IRS may be triggered after initiation of HAART or
after the change to a more active therapy as it was seen in
our patient. The most immunosuppressed patients with a
CD4 T cell count less than 100 cells/ml treated with the
most potent regimens, particularly PIs, resulting in signi-
ficant HIV viral load declines, are at greatest risk for the
development of IRS after HAART initiation [8].
In 1998, Gilquin et al. reported the occurrence of au-
toimmune hyperthyroidism in 3 patients with HIV after
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Graves’ Disease as a Late Manifestation of Immune Reconstitution Syndrome
after Highly Active Antiretroviral Therapy in an HIV-1 Infected Patient 189
16 - 22 months of beginning HAART [9]. Two years
later, Jubault and Gilquin analyzed the relationship be-
tween thyroid autoantibodies, GD and immune restora-
tion on HAART in five patients (median age, 41 yr).
They found that GD diagnosis coincided with a great rise
of the CD4 T-cell count. Anti-thyroid autoantibodies
were absent before immune restoration with HAART and
appeared 14 months after starting HAART. GD was di-
agnosed 18 months after the CD4 T-cell count had raised
and 20 months after starting HAART [5].
Chen et al. published an ob serv ation al study in 2005 in
which 17 patients developed autoimmune thyroid disease
(AITD) and GD was diagnosed in 15 of them. These pa-
tients were predominantly female (82%), of black ethnic-
ity (65%) and the median age were 38 years. They were
compared with a contro l group who started HAART dur-
ing the same time and did not developed clinical AITD.
The AITD group had a significantly lower mean baselin e
CD4 count compared with the control group (66.6 cells/
µL versus 218.8 cells/µL) and a higher rise in CD4 T-
cells count (355.1 cells/µL versus 199.6 cells/µL). More
patients in the AITD group were severely compromised
at base line th an con tro ls. Memo r y CD4 T- cells in cr eas e a
few weeks to months after commencement of HAART
by redistribution from the lymphoid tissues, phase in
which can appear opportunistic infections follow by a
rise of naive CD4 T cells of thymic origin, from 6 months
to years. All patients developed AITD in the phase of
naive T cell reconstitution [10].
The inmunopathogenesis of GD after the substantial
increased of T-cells because of HAART, might result
from an acquired defect of central T cell tolerance re-
sulting from thymus dysfunction [11], defects of periph-
eral T cell tolerance expressed by abnormal function of
the T cell immunoregulatory receptor cytotoxic T lynpho-
cyte antigen 4 (CTLA-4) [12,13] and “molecular mim-
icry” because of a structural similarity between microbial
and self-antigens that could have a key role in activating
autoreactive T cells [14,15]. GD after HAART in HIV pa-
tients may result from failure to delete auto-reactive T
cell clones because of the intense regeneration in the thy-
mus [11].
Patients with sustained virological responses to
HAART had a rise of soluble CTLA4 that could compete
with membrane-bou nd CTLA-4 for CD80/CD86, in later
T lymphocytes activation phase, causing a reduction of
inhibitory signal enhancing the immune response [12,
Among the reported cases (Table 2 ) the mean age was
36.7 years, the mean CD4-T cells count increased from
nadir to the development of GD was 394.5 cell/µL and
the mean time from starting HAART to the diagnosis of
GD was 26 months (range 9 - 53). All patients were
treated with antithyroid drugs, some of them required
I131 treatment lately and only a few were thyroidecto-
mized [5,9-11,16-21]. In our case, radioablation therapy
was not an option because of the exophthalmos presence
and we decided to begin methimazole in spite of the ap-
lastic anemia low risk.
Our patient developed GD 36 months after initiating
effective HAART with protease inhibitors which was
coincident with viral suppression and a rise of CD4 T
Table 2. Reported cases of Graves’ disease after IRS.
Cases Mean CD4 cell Time to Treatment (cases No) Reference
No. Age Change GD Antithyroid I-131 Surgery Year
(Years) (Cells/ml) (Months) Drugs
3 39 25 - 287 18 3 1 - 1998, Gilquin
5 37 18 - 297 20 NR NR NR 2000, Jubault
6 38 104 - 533 20 NR NR NR 2004, Wong
1 39 0 - 600 32 1 1 - 2004, French
15 39 45 - 430 17 15 - - 2005, Chen
5 43 11 - 291 17 5 - 2 2006, Crum
1 27 12 - 623 36 1 - - 2006, Knysz
3 NR 0 - 410 25 3 3 - 2006, Vos
2 30 NR - 77 39 2 2 - 2007, Pinto
4 39 59 - 397 37 4 1 - 2011, Rasul
NR, not reported; -, not done; GD, Graves’ disease; IRS, Immune Reconstitution syndrome.
Copyright © 2013 SciRes. WJA
Graves’ Disease as a Late Manifestation of Immune Reconstitution Syndrome
after Highly Active Antiretroviral Therapy in an HIV-1 Infected Patient
cells from less than 100 to 343 cells/µL, being that an
infrequent but recognized late presentation of the Im-
mune Reconstitution Syndrome in mostly immune sup-
pressed HIV patients.
4. Conclusion
The most immunosuppressed patients with a CD4 T cell
count < 100 cells/ml treated with the most potent regi-
mens, particularly PIs, resulting in significant HIV viral
load declines are at greatest risk for the development of
IRS after HAART initiation [8]. Even though it is an
uncommon manifestation of IRS, we think that Clini-
cians will have to consider the importance of the early
diagnosis to bring an adequate treatment and to decrease
the associated morbidity of Graves’ disease.
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