Prevalence of nephropathy and proximal tubule disorder in human immunodeficiency virus patients under tenofovir therapy

Implication for health policy/practice/research/medical education: This study reflects complications related to administration of tenofovir in human immunodeficiency virus (HIV) patients and could serve as a practical guide for HIV specialists in administration of HIV antiviral therapy. Please cite this paper as: Sabzghabaei F, Sedighi A, Shahi R, Mahmoodi V, Khamseh J, Rahimian N. Prevalence of nephropathy and proximal tubule disorder in human immunodeficiency virus patients under tenofovir therapy. J Nephropharmacol. 2022;11(1):e11. DOI: 10.34172/npj.2022.1


Introduction
Human immunodeficiency virus (HIV) is one of the most common fatal infectious diseases found worldwide and the highly active antiretroviral therapy (HAART) is the most recommended therapeutic option for these patients (1). However, no single therapy is approved for HIV patients (1,2). Tenofovir is a nocloside transcriptase inhibitor acting via interaction with function of RNArelated DNA polymerase, leading to viral inhibition and it is a first-line HIV treatment in many countries in patients with urinary excretion (1,2).

Objectives
Tenofovir is a common therapy in HIV patients, and nephropathy is its main therapeutic adverse effect. Hence, considering the necessity for the preservation of renal function in these patients amidst scarcity of studies on Iranians, this study was conducted to determine prevalence of nephropathy and proximal tubule disorder in HIV patients under tenofovir therapy in Iran.

Study design
In this cohort, 160 consecutive HIV patients under tenofovir therapy from September 2018 to April 2020 were enrolled. The exclusion criteria were chronic kidney disease stage 4 and end-stage renal disease. Data were collected through a checklist. The variables included age, gender, age of onset, duration of treatment, background diseases, smoking, alcohol use, drug/opium use, vital signs, glomerular filtration rate (GFR), creatinine, urea, uric acid (UA), sodium, and potassium. The UA, creatinine, and urea were checked every three months. In cases with increase in creatinine, the tenofovir was discontinued, and the effect on GFR level was assessed. The prevalence of nephropathy and proximal tubule disorder was determined in patients and was compared by other variables.

Data analysis
Data analysis was carried out by the SPSS version 25.0 software. The different types of tests employed included ANOVA, Chi-squared, independent sample t test, and post-hoc Tukey's assays. P values under 0.05 were considered as statistically significant.

Results
In this study, 101 (63.1%) patients were male and the mean (standard deviation) age was 43.3 years (11.2 years) (range; 9-72 years). In total, 82 cases (51.3%) were married. The mean (standard deviation) body mass index (BMI) was 24.9 kg/m 2 (4.5 kg/m²). Around 31 cases (19.4%) had academic literacy. Duration of HIV in "less than five years", "between 5 and 10 years" and "more than 10 years" were in 42.5%, 29.3% and 18.2% of subjects respectively. However, the average duration was 6.6 years (4.3 years). As shown in Table 1, the main transmission route was sexual relationship (45%). Continuous non-steroidal anti-inflammatory drug (NSAID) use over the last year was reported in 60.6% of cases and 30% of cases were smokers too. In addition, 1.9% of patients were also using intravenous opioids. The history of background diseases is shown in Table 2. The mean serum creatinine was 0.96 mg/dL, 0.98 mg/dL and 1.09 mg/dL in baseline, after six months and at the final stage, respectively. GFR decrease was one of the causes of tenofovir discontinuation in 55% of cases. The other causes are shown in Table 3. The laboratory results are shown in Table 4.
The first and second therapeutic regimens in patients are shown in Table 5. The mean GFR initially was 89.98 (17.78) and the finally 77.95 (18.62), showing a significant difference (P = 0.001). The GFR level lower than 90 mg/dL was increased by 74.4%.
There was GFR decrease in 84.4% of cases compared with measurements conducted before the treatment. In total, 13.1% of the patients had proteinuria, including 1+, 2+ and 3+ in 8.8%, 2.5% and 1.9% of cases, respectively. The GFR alteration rates are shown in Table 6. Only inhalational opium use (P = 0.001), as shown in Table 7, was related to GFR alterations in patients. The mean CD4 count was initially 389.28 (334.08), and the final mean GFR level was 620.94 (284.24), showing a significant difference (P = 0.001). CD4 count was increased by 83.1%, with a mean increase of 319.4 (188.6) and mean decrease of 235.24 (422.29). There was a significant correlation between CD4 count and GFR level (P = 0.001).

Discussion
In this study, the rate and extent of nephropathy due to tenofovir use was determined in HIV-positive cases.
Proximal tubule disorders were seen in 25%, 6.8% and 2.2% in the first year, at 2-5 years, and at 6-10 years of tenofovir use; however, thereafter no cases were seen until 18 years later. It was related to duration of use. The mean rate of GFR    Sabzghabaei F et al adverse effects (13). Moreover, Weaver et al, reported that of 24 HIV-positive cases under tenofovir therapy, 42% had reversible outcomes (3). However, in our study with a larger same size, the irreversible cases were more common. In another study on 213 Brazilian patients, the cardiovascular disease rate was higher in cases undergoing tenofovir therapy (4). However, in our study, no comparison was conducted with other drugs due to some limitations. In the study by Waheed et al, on 15 cases under tenofovir therapy, of total patients, 11 patients had GFR more than 90 and the duration of treatment was considered 64 months (5). The mean GFR was decreased from 104 mL/min to 69 mL/min and then it was improved but not completely after drug discontinuation. This similarly shows the irreversible pattern. Herlitz et al, reported a rate of 61% for acute kidney injury and 15% for anuria (6). The difference in results of their survey may be due to a smaller sample size compared with our study.
A cross-sectional study on 101 patients showed that creatinine rise, proteinuria and tubular dysfunction were present in 7%, 37% and 15% of cases, respectively (7). However, these rates were lower in our study due to a shorter follow-up length. Gerard et al, assessed 53 patients under tenofovir therapy for 13 months (8). They found, GFR was decreased at a rate of 7.8 mL/min versus the control group. However, we had no control group for comparison and such design may be pursued in future studies. Crane et al reported a mean GFR decrease rate of 7 mL/min, leading to a rate of less than 60 ml/min in 2% of cases, similar to our study (9).
A review study by Jafari et al showed that older age, opium or NSAIDs use, low weight, low CD4+ count and high-dose and long-term tenofovir therapy were related to renal disorders in HIV cases under tenofovir therapy (14). Among these factors, only low CD4 cell count was related to nephropathy. Liu et al assessed 823 adult cases with GFR over 90 ml/min. They found, 21.6% had renal failure with an S-shaped pattern of renal function (15). The difference was especially higher between the first and fourth year of tenofovir therapy. Hence, tenofovir may be administered in the first year of treatment and then replaced with other agents.
Hoang et al reported that 8.5% out of 400 cases under tenofovir therapy had renal dysfunction that was related to older age, lower BMI and no exposure to isoniazid therapy (16). Anthropometric and demographic variables and tuberculosis treatment in our study were not related to renal function. Accordingly, Gupta et al, showed the importance of the type of salt used in tenofovir. This may be a possible cause of differences between results of various studies (17).

Conclusion
In this study, we concluded that GFR diminution and proximal tubule involvement are common and important to be managed in HIV-positive patients under tenofovir therapy, since discontinuation of the drug has no positive effect on GFR. Regarding the results, treatment with tenofovir in the initial two years is rational and then replacement with other drugs may be considered. However, further studies with a larger sample size and multi-center sampling can lead to more definitive results.

Limitations of the study
Main limitations of our study are a smaller sample size and a shorter patient follow-up period. Further studies with a larger sample size and long-term-follow up are recommended.
Authors' contribution AS, FS and KE were the principal investigators of the study. RS, JKh, VM and NR were involved in preparing the concept and design of this study. VM and JKh revisited the manuscript and critically evaluated the intellectual contents. All authors participated in preparing the final draft of the manuscript, revising the manuscript and critically evaluating the intellectual contents. All authors have read and approved the content of the manuscript and confirmed the accuracy or integrity of any part of the work.