DISCUSSION:
With the features like high efficacy, good tolerability, a favorable
safety profile, and the absence of significant drug-drug interaction,
Integrase inhibitors are now recommended as the preferred first-line
regimen for people living with HIV initiating antiretroviral
therapy.6,7 They are a class of antiretroviral
medications that act by blocking the integrase enzyme responsible for
integrating double-stranded DNA into the host cell genome thus
inhibiting HIV from multiplying and infecting other
cells.8
Dolutegravir, which was approved in 2013, is the most recent integrase
inhibitor that is equally effective as or better than current treatment
regimens in both treatment-experienced and treatment-naive individuals.9 Common adverse effects include headache, nausea, and
diarrhea. With Dolutegravir, there is no increase in triglycerides,
low-density lipoprotein, or total cholesterol that is seen with Protease
inhibitors.10
In our case, the patient developed the features of anemia like fatigue,
generalized weakness, and shortness of breath after taking Dolutegravir
(DTG) along with Tenofovir disoproxil fumarate (TDF) and Lamivudine
(3TC) for two months. Initially, iron deficiency anemia was suspected
and so baseline investigations along with iron profile were sent. But
the serum ferritin level was high. Peripheral blood smear, Anti-nuclear
antibody test, Direct Coomb’s test, and chromosomal analysis were also
done. Considering the possibility of sideroblastic anemia, bone marrow
aspirate and biopsy were planned. Sideroblastic anemias include a
heterogeneous group of inherited/congenital and acquired disorders
characterized by ineffective erythropoiesis and the presence of ring
sideroblasts in the bone marrow aspirate. Ring sideroblasts, aberrant
erythroblasts with iron-loaded mitochondria, are seen as a perinuclear
ring of green-blue granules when stained with Prussian
blue.2 There should be a minimum of 5 granules
encircling one-third of the nuclear diameter in this Prussian blue
staining process known as the Perls reaction.11Sideroblastic anemias can be grouped into inherited and acquired forms.
The inherited forms are rare and characterized by three modes of
inheritance: X-linked (XLSA), autosomal recessive (ARSA), or maternal.
Acquired sideroblastic anemias can be classified into clonal
(neoplastic) and nonclonal (nonneoplastic). 12,13Nonclonal, acquired sideroblastic anemias can be encountered in the
setting of alcohol addiction and associated pyridoxine deficiency and
are typically caused by dietary deficiencies or ingestion/accumulation
of toxins.14 Alternative reasons include copper
deficiency15 and medications including
chloramphenicol, linezolid, penicillamine, busulfan, melphalan, and
cycloserine (due to pyridoxine deficiency).11,16,17
Although the prevalence of sideroblastic anemia has not been defined, it
is rare.12 Regardless of the genetic variety and
pathophysiologic variation among sideroblastic anemia subtypes, the
diagnostic approach for sideroblastic anemia adheres to the same
fundamental ideas. Before doing a clinical and genetic examination for
congenital sideroblastic anemia, reversible causes of sideroblastic
anemia and myelodysplastic syndrome must be ruled out. By definition,
iron staining in the bone marrow aspirate is necessary for the diagnosis
of all kinds of sideroblastic anemia. Excessive alcohol use, heavy metal
toxicity, isoniazid, chloramphenicol, or linezolid treatment,
malnutrition with following copper, vitamin B6, or thiamine
deficiencies, as observed after bariatric surgery, are all reversible
factors that should be carefully examined while eliciting a
history.12 When reversible causes of sideroblastic
anemia are considered, one must take into account atypical connections
that patients might not be aware of. For example, prolonged high-zinc
consumption from fad diets or routine use of zinc-containing denture
treatments may not be evident causes of zinc poisoning and hemolytic
anemia. This justifies including copper, ceruloplasmin, zinc, and lead
levels in the diagnostic assessment even in situations when there isn’t
a clear connection. In our patient, we ruled out these reversible causes
by taking a detailed medical history, family history, personal history,
and physical examination. During the first three years of continuing the
Tenofovir Disoproxil Fumarate (TDF), Lamivudine (3TC), and Efavirenz
(EFV) regimen, the patient never complained of symptoms of anemia like
generalized fatigability, shortness of breath, weakness, etc. But after
two months of introduction of Dolutegravir into the ART regimen, the
symptoms of anemia started.
Whatever reversible cause might be causing sideroblastic anemia in this
patient, removal of the offending agent is the first step of its
management. In our case, the patient’s condition improved after stopping
dolutegravir for a month. During a later six-month monitoring period,
there was a sustained hematologic improvement without a recurrence of
anemia. This discontinuation, along with the clinical presentation and
bone marrow aspirate findings suggested dolutegravir as the reversible
cause of acquired sideroblastic anemia.