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Incidence and Risk Factors of Hypophosphatemia in Patients with HIV Infection Receiving Tenofovir Disoproxil Fumarate; a real practice report from a Hospital Belonging to a Medical Service Department

HIV Abstract This retrospective cross-sectional study aimed to estimate the incidence and risk factors of hypophosphatemia in patients receiving TDF-containing anti-HIV regimens. Data of patients with HIV infection who received TDF between July 1, 2018, and June 30, 2020, at a hospital belonging to a medical service department were reviewed. Data such as serum creatinine and serum phosphate levels were collected from medical records and electronic medical records and then transferred through a data record form. Hypophosphatemia was defined as serum phosphate value lower than 2.5 mg/dL. As a result, from 798 cases of patients with HIV infection who received TDF, 26 patients met the inclusion criteria and five patients had hypophosphatemia (19.2%), and the standard drug dose was used (300 mg/day) or was properly adjusted according to patients’ renal function. The median duration of TDF use was 10 (1–63) months. Other factors that may contribute to the development of hypophosphatemia are comorbidities and other drugs; there was one patient who used antacids longer than 1 week before onset of hypophosphatemia. This study may help develop a risk assessment tool for monitoring hypophosphatemia in patients who received TDF.


Introduction
Tenofovir disoproxil fumarate (TDF) is one of most commonly used antiretroviral medication in patients with HIV infection. Owing to its widespread application, studies have reported its side effects [1][2]. The most common adverse effect of TDF is nephrotoxicity [3][4][5][6]. Hypophosphathemia also occurred in most cases with TDF before nephrotoxicity was detected. Appearance can demonstrate the relationship between hypophosphatemia and nephrotoxicity [7]. As a result, the use of hypophosphatemia as a monitoring tool in routine practice is limited, but results of previous studies were controversial [8]. The incidence of hypophosphatemia ranged from 9% to 30% [5][6][7][8][9][10]. To our knowledge, no study in Thailand has examined the incidence of hypophosphatemia, but only a study on the incidence of tenofovir isoproxil fumarate-induced proximal tubulopathy in patients with human immunodeficiency virus (HIV) infection found that 9.2% of patients had hypophosphatemia [5]. Therefore, this study aimed to determine the incidence of hypophosphatemia in patients with HIV infection receiving TDF and to explore the risk factors of TDF-induced hypophosphatemia.

Abstract
This retrospective cross-sectional study aimed to estimate the incidence and risk factors of hypophosphatemia in patients receiving TDF-containing anti-HIV regimens. Data of patients with HIV infection who received TDF between July 1, 2018, and June 30, 2020, at a hospital belonging to a medical service department were reviewed. Data such as serum creatinine and serum phosphate levels were collected from medical records and electronic medical records and then transferred through a data record form. Hypophosphatemia was defined as serum phosphate value lower than 2.5 mg/dL. As a result, from 798 cases of patients with HIV infection who received TDF, 26 patients met the inclusion criteria and five patients had hypophosphatemia (19.2%), and the standard drug dose was used (300 mg/day) or was properly adjusted according to patients' renal function. The median duration of TDF use was 10 (1-63) months. Other factors that may contribute to the development of hypophosphatemia are comorbidities and other drugs; there was one patient who used antacids longer than 1 week before onset of hypophosphatemia. This study may help develop a risk assessment tool for monitoring hypophosphatemia in patients who received TDF.

Research design
This retrospective cross-sectional study was carried out to determine the incidence of hypophosphatemia in patients with HIV infection receiving TDF.

Population
The study population comprised patients with HIV infection who received TDF and visited the hospital between July 1, 2019, and June 30, 2020.

Inclusion criteria
• Receiving TDF at least 1 month • Age >18 years • Assessment of SCr before and after 1 month of receiving TDF as baseline values • Serum phosphate levels were monitored before and after 1 month of receiving TDF as baseline value • Continuous monitoring of SCr and serum phosphate at least once after receiving TDF • Antiretroviral therapy with dose modified according to renal function by considering creatine clearance

Exclusion criteria
• Patients who withdraw from the study or died of causes other than hypophosphatemia.
• Patients who stopped using TDF for reasons other than hypophosphatemia.
The cutoff value of hypophosphatemia was serum phosphate below 2.5 mg/dL.

Data collection
The data collection form consisted of the following information: • Demographic data • Treatment information • Laboratory information before and after receiving TDF, Scr, and serum phosphate • Other factors that affect serum phosphate level (such as alcoholic cirrhosis, malnutrition, Crohn's disease, severe vomiting, steatorrhea, chronic diarrhea, diabetic ketoacidosis, and infection) and use of drug-induced hypophosphatemia (increase phosphate excretion: adefovir, ifosfamide, cefepime, and ceftolozane/tazobactam; increase phosphate absorption: antacid, high-dose niacin, and acetazolamide) were recorded.

Data analysis
The incidence of hypophosphatemia was calculated using the following formula: Incidence of hypophosphatemia = Factors associated with hypophosphatemia were analyzed by multivariate regression with level of significance set at 0.05.
This study was approved by the ethics committee of Silpakorn University, Nakhon Pathom, Thailand (REC 631012-1205118), and the local hospital (Ratphiphat Hospital ethic committee.

Demographic data
A total of 26 patients were recruited, and most of the patients were male (76.9) with median weight of 59 kg. The median duration of using TDF was 28.5 months. The median serum creatinine and serum phosphate levels at baseline were 0.8 mg/dL and 4.1 mg/dL, respectively. Only one patient had concomitant drug that can cause hypophosphatemia ( Table 1).

Incidence of hypophosphatemia
In the data collection, 798 patients with HIV infection received TDF. However, 774 patients did not meet the inclusion criteria. Approximately 50% of these patients did not have serum phosphate measurement at baseline. Therefore, 26 patients were recruited, of which five patients had hypophosphatemia (1). The calculated incidence is 19.2 and median duration of receiving TDF until hypophosphatemia occurred is 10 months as presented in  Table 3 summarizes data of five patients who received TDF and developed hypophosphatemia.

Cases of hypophosphatemia
All patients did not have comorbidity. The suspected comedication that could have caused hypophosphatemia was not identified, except in patient 2 who received antacid with TDF for 8 weeks, following which hypophosphatemia occurred. All patients took 300 mg of TDF at bedtime, or the dose was adjusted according to their renal function. The serum phosphate level returned to normal values in patients 1, 3, and 4 within 1 week, 3 days, and 1 month, respectively, without any intervention.

Incidence of hypophosphatemia
The incidence of hypophosphatemia in this study was similar to that in a previous study [6] of 145 patients with HIV infection, which also reported a relationship between nephrotoxicity and increase risk of severe renal tubular damage despite normal serum creatinine level. The mean duration of using TDF until hypophosphatemia occurred was 11+ 9 months, and the incidence of hypophosphatemia was 26%. Hypophosphatemia could be explained by the mechanism of TDF that induces renal tubular damage by decreasing mitochondria function, which leads to Fanconi syndrome and disrupted phosphate absorption because of phosphaturia [10,12].

Risk factors of hypophosphatemia
Previous studies have investigated risk factors of hypophosphatemia [13][14][15][16][17], and factors are classified as comorbidity factors and comedication factors [15][16][17]. Comorbidities that affect serum phosphate levels are alcoholism, malnutrition, Crohn's disease, severe vomiting, steatorrhea, diabetic ketoacidosis, and sepsis. Comedications that influence serum phosphate level include adefovir, ifosfamide, cefepime, and ceftolozane/tazobactam which can increase phosphate excretion. Nevertheless, some medications interfere with phosphate absorption, such as antacids, highdose niacin, and acetazolamide [15][16][17]. In this study, only one patient had one risk factor; the patient was also taking antacid. Given the small sample size, this study could not use statistical methods to evaluate or explore significant factors that influence hypophosphatemia. Although nearly all cases did not have evidence of risk factors that increase the risk of hypophosphatemia, undetermined risk factors may have existed, such as poor nutrition status which is not usually evaluated in routine practice.
This study has some limitations. First, data may have been insufficient and incomplete owing to the retrospective collection of data. Therefore, the calculated incidence and onset of events were only estimated from existing data. To confirm this value, a prospective study is warranted. Second, given the small sample size, further statistical analysis was not performed to determine significant factors associated with hypophosphatemia regardless of TDF.

Acknowledgement
The researchers thank the kind cooperation of all staffs. In