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.