INTRODUCTION

Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) are some of the major public health problems around the world, in particular, in the developing countries of Africa and southeastern Asia. The number of new cases has declined significantly after highly active antiretroviral therapy (ART) and intensive information, education and communication (IEC) strategies have been implemented. However, India is still estimated to have the third-largest HIV-infected population in the world, after South Africa and Nigeria, with an estimated adult prevalence of 0.22% (0.16–0.30%) in 2017 [1].

Anemia is an important cause of morbidity in HIV-infected individuals around the world, irrespective of highly active ART, which significantly improves quality of life and prevents the progression of HIV disease [2,3]. The acceleration of the disease, a decreased life expectancy, impaired physical function, the risk of ART-associated hepatotoxicity, psychological distress, and poor quality of life are important consequences of HIV-associated anemia [4–6].

The prevalence of HIV-associated anemia ranges from 10% in asymptomatic HIV disease to 92% among individuals with advanced AIDS and is 24% and 58% in individuals taking ART and up to 35% in those ART-naïve [4,7–10]. However, it may occur at any stage of HIV disease, with a severity that may correlate with the progression of the disease with a higher prevalence among ART-naïve individuals when compared to those taking ART [11,12]. A multitude of factors, such as sex, low nutritional status, anti-tuberculosis treatment (ATT), opportunistic infections, an advanced stage of the HIV disease, a CD4⁺ count below 200 cells/microliter, a white blood cell (WBC) count below 4000 cells/microliter, and a platelet count below 200,000 cells/microliter, as well as zidovudine-containing ART regimens, have been identified to be associated with anemia among HIV-affected individuals [8,4,13–16]. Pure red cell aplasia, characterized by a normal leukocyte and platelet count, a corrected reticulocyte count below 1%, less than 5% of erythrocyte precursors in the bone marrow, and no hemolysis is an uncommon cause of refractory anemia in HIV/AIDS and occurs consequent to an autoimmune response selectively affecting erythroid cell lines or ART-induced myelosuppression [16–18]. However, the magnitude of these factors varies across regions depending upon socioeconomic and health conditions. Although the prevalence of anemia among the HIV-affected and the associated factors remain understudied in the Indian context, it was 23% to 61.5% in some studies, irrespective of their ART status [6,18–20]. Since the management of anemia in these individuals improves survival and the overall quality of life, we performed this study with the aim to assess the prevalence of anemia and the associated factors in HIVinfected individuals under follow-up in this part of the country having a low prevalence of HIV/AIDS and for an overall paucity of relevant data.

MATERIALS AND METHODS

The medical records of 518 patients on regular ART registered in the institute-affiliated ART Center and under follow-up between January 2015 and December 2019 were analyzed retrospectively for this hospital-based, descriptive, observational study after obtaining approval from the Institutional Ethics Committee. Sociodemographic details, the CD4⁺ count, previous illnesses and their treatment (if any), hemoglobin (Hb) levels, and the results of complete blood counts recorded before the initiation of ART together with the most recent one were noted from their ART records or booklets maintained in the center. Hemoglobin levels of at least 12 g/dL were considered normal and anemia was defined per the WHO guidelines as hemoglobin values below 13 g/dL in adult males, below 12 g/dL in adult females, below 11 g/dL in children below five years of age, and below 11.5 g/dL in children between five to eleven years of age [21]. The severity of anemia was graded as mild with Hb = 11.0−11.9 g/dL, as moderate with Hb = 8.0−10.9 g/dL, and as severe with Hb < 8.0 g/dL.

RESULTS

Table 1 shows the baseline characteristics of the 513 study subjects, comprising 244 (47.6%) males and 269 (52.4%) females (M: F: 0.9:1) aged between 12 and 84 years (mean ± SD: 37.5 ± 12.1 years). Among the subjects, 380 (74.1%) were aged 16–45 years. The CD4⁺ cell count varied from 5 to 1824 (mean ± SD = 240.12 ± 187.94) cells/microliter and were ≤ 200 cells/microliter in 252 (49.1%) individuals. All had been on highly active ART with good treatment adherence for two weeks to nine years and four months (mean: 3.15 years), and 395 (77%) individuals had been undergoing treatment for not longer than five years. The major ART regimens were tenofovir + lamivudine + efavirenz (TLE) in 282 (55%), zidovudine + lamivudine + nevirapine (ZLN) in 177 (34.5%), and zidovudine + lamivudine + efavirenz (ZLE) in 22 (4.29%) individuals, respectively. Overall, 199 (38.8%) had been taking zidovudine-containing ART regimens. Six (1.2%) developed nevirapine hypersensitivity syndrome and the initial nevirapine-based ART regimens were changed to a tenofovir + lamivudine + efavirenz (TLE) regimen. Thirty (5.8%) received anti-tuberculosis treatment (ATT) for pulmonary tuberculosis in a recommended dose and schedule before ART was initiated. The only individual with an HBV co-infection had not received any drug(s) other than ART. Laboratory reports for the leukocyte and platelet count were available only for 492 and 451 cases, respectively. Information for body weight/BMI, iron supplements, alcohol abuse, and the presence of concurrent or opportunistic infections or their treatment and prophylaxis, particularly for Pneumocystis jiroveci pneumonia, was not available in the records.

Table 1: Baseline characteristics of the patients.

Hemoglobin levels varied from 4.4 to 16.5 g/dL (mean ± SD: 10.8 ± 2.02 g/dL). Three hundred and sixty-eight (77.7%) individuals had anemia before the initiation of ART, which was mild in 72 (13.9%), moderate in 257 (50.2%), and severe in 39 (7.6%) cases, respectively. The female sex (OR: 2.09; Cl: 95%; CI: 1.41–3.10; p < 0.05), a CD4⁺ count ≤ 200 cells/microliter (OR: 2.36; Cl: 95%; CI: 1.59–3.52; p < 0.0001), a WBC count < 4000 cells/mm³ (OR: 3.29; Cl: 95%; CI: 0.97–11.14; p < 0.04), a platelet count < 100,000 cells/mm³ (OR: 0.50; Cl: 95%; CI: 0.31–0.81; p < 0.05), before the initiation of ART (OR: 3.78; Cl: 95%; CI: 2.91–4.91; p < 0.0001), ATT intake (OR: 5.88; Cl: 95%; CI: 1.38–25.04; p < 0.05), and nevirapine hypersensitivity (OR: 0.38; Cl: 95%; CI: 0.07–1.95; p < 0.04) were significantly associated with anemia (Table2). However, zidovudine-containing ART regimens were not found to be significantly associated with anemia (OR: 0.71; Cl: 95%; CI: 0.49–1.02; p = 0.067). Meanwhile, ART significantly improved hemoglobin levels and corrected anemia, as only 206 (40%) individuals had anemia after ART, as opposed to 368 (77.7%) with anemia before the initiation of ART (p < 0.0001).

Table 2: Factors associated with anemia.

DISCUSSION

The demographic profile of HIV-affected individuals in this study was similar to what has been described in the past [6,22]. The prevalence of anemia ranged between 10% to 28% in asymptomatic HIV-infected individuals in the pre-AIDS stage and 71–92% in those with AIDS across countries [6,9–11,13]. In general, the prevalence of anemia was higher in those ART-naïve than those on ART, and severity varied from mild to severe [4,9,11–13]. In a recent study, it was mild in 13%, moderate in 14%, and severe in 7.4% of cases, respectively [11]. In our study, the prevalence of anemia was 77.7% before ART was initiated, which was moderate in almost half of the cases, as opposed to mild in 13.9% and severe in 7.6% of the individuals. The prevalence decreased to 28.3% after ART, conforming to the above epidemiological trends. Apart from anemia of a chronic disease, HIV-associated anemia may be due to nutritional deficiencies, blood loss, medication-induced hemolysis, or bone marrow suppression (trimethoprim–sulfamethoxazole, zidovudine, amphotericin) [18]. The female sex, a CD4⁺ count below 200 cells/microliter, and ATT intake were other significant factors associated with anemia in this study. These observations suggest that HIV infection by itself is an important cause of anemia in the majority of the HIV-affected. HIV infection is believed to affect bone marrow functioning directly or from opportunistic infections especially during the early phase of uncontrolled HIV multiplication, or because of drug toxicity over a period of time [20]. Anemia in individuals before the initiation of ART, a WBC count below 4000 cells/mm³, and thrombocytopenia (platelet count < 100,000/mm³) in this study, as well as the other significant factors (p < 0.5) associated with anemia, also reflect some amount of HIV-induced myelosuppression. However, none of our patients were pregnant, had chronic renal failure, or received a blood transfusion for severe anemia or blood loss. Individuals with a low CD4⁺ cell count have a high viral load and are at an increased risk for opportunistic infections, which in turn may lead to an increased prevalence of anemia. Concurrent opportunistic infections (parvovirus B19, Pneumocystis jiroveci, tuberculosis, Mycobacterium avium complex) and their therapies, for instance, tuberculosis, due to chronicity, bone marrow suppression, malnutrition, and hemoptysis, and any severe drug toxicity (including from nevirapine) possibly enhance the risk of anemia in these individuals, as was observed in this study [11,15,18]. An improvement in anemia after ART, as in this study, is due to the suppression of the viral replication/load and improved immunity against opportunistic infections and the overall gain in health reinforcing the foregoing [13]. Although zidovudine-containing ART regimens, especially the during the early phase of ART initiation, have been identified to be associated with anemia, especially among individuals with low baseline hemoglobin and pure red cell aplasia in particular, we made no such observations, as individuals with low Hb were not put on zidovudine-containing regimens [13,16,23]. However, only a small number of individuals were on zidovudine-containing ART for a meaningful conclusion and may not reflect the real effect of zidovudine. In our study, details on other risk factors of anemia, such as Pneumocystis jiroveci prophylaxis and the nutritional status of the HIV-affected, could not have been ascertained from the records

CONCLUSION

Anemia may be a significant co-morbidity among HIV-infected individuals, especially in females, before the initiation of ART, and those with a CD4⁺ count ≤ 200 cells/microliter, a WBC count < 4000 cells/mm³, thrombocytopenia, a history of nevirapine adverse reactions, or ATT intake. While 50% of affected individuals may have moderate anemia, the spectrum varies from mild to severe anemia, necessitating screening for the overall health of the affected individual. ART significantly improves pre-existing HIV-associated anemia in the majority. The low potential of zidovudine-containing regimens for ART-associated anemia perhaps does not reflect the real effect of zidovudine because of the small number of these cases. Well-designed and prospective studies addressing the limitations of this study are highly desirable to further our understanding of factors associated with anemia and its effect on the overall health of the HIV-affected and the interventions needed.