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Abstract

The use of tenofovir disoproxil fumarate (TDF) is supposed to be increased in a resource-limited setting due to the changing of the guidelines. TDF–associated renal function declines among HIV-infected patients were defined by an increase of serum creatinine (SCr) >1.5 times, a 25% decrease in calculated creatinine clearance (CCrCl), or an estimated glomerular filtration rate (eGFR) from the baseline. Of all, 99% were antiretroviral treatment (ART)-experienced patients. At the 30th month, 19 (5.3%), 53 (14.9%), and 63 (17.7%) patients had renal function decline as defined by the above criteria with an incidence of 4.5, 12.5, and 14.6/100 person-year. A proportion of patients with a renal function decline detected by CCrCl or eGFR criteria was not different (P = .301), whereas, it differed from that detected by SCr criteria (P < .001). In conclusion, we encourage either CCrCl or eGFR calculations in monitoring renal function decline among HIV-infected patients receiving TDF in resource-limited settings.

Keywords

creatinine clearance glomerular filtration rate HIV renal function tenofovir

Introduction

Tenofovir disoproxil fumarate (TDF) has been approved by the US Food and Drug Administration for the treatment of HIV infection since 2001. This drug has been available and widely used in many countries including resource-limited ones in subsequent years. According to the updated antiretroviral guidelines, TDF is recommended as one of the drugs in the preferred antiretroviral regimen for the treatment of HIV infection in adults and adolescents^1–4 because of its efficacy, a lesser pill burden, less fat redistribution, and dyslipidemia compared to other nucleoside reverse transcriptase inhibitors.⁵ Use of TDF for the treatment of HIV infection is supposed to be increased in resource-limited countries, due to the changing of the guidelines.

Generally, TDF is well tolerated and the frequency of adverse effects is low.⁶ Nephrotoxicity-associated TDF is uncommon but concerns have recently arisen, given that another 2 monophosphate nucleoside analogs, adefovir and cidofovir, are well-known nephrotoxic agents.⁷ The reported incidence of TDF-associated nephrotoxicity was similar among the TDF and comparator group in the clinical trials.⁸ However, reports describing nephrotoxicity attributable to TDF in HIV-infected patients have been increasingly published, such as changes in renal function (either glomerular or tubular function), acute renal failure, Fanconi syndrome, or nephrogenic diabetes insipidus.^9–13 This is because TDF is eliminated by renal clearance, largely by glomerular filtration, with 20% to 30% being actively transported into renal proximal tubule cells.⁷

Several biomarkers are available for monitoring of renal function, although no consensus exists on how best to apply these methods for HIV-infected patients. Accurate glomerular filtration rate (GFR) estimation is essential for the detection and management of kidney disease and for dosing and monitoring adverse effects associated with antiretroviral therapy (ART).¹⁴ Creatinine-based estimates of GFR are widely used in clinical practice owing to its easy availability and inexpensiveness.¹⁴ In addition, creatinine-based estimates is also best converted into creatinine clearance (CrCl) or estimated GFR (eGFR).¹⁴ Using the different methods for the monitoring of renal function might create variation of the results regarding the incidence and risk factors for TDF-associated nephrotoxicity among HIV-infected patients who are currently receiving this drug. Some cohort studies described no significant evidence of renal dysfunction with the use of TDF^15–17 in contrast to the other study.⁹

Most of HIV-infected patients’ care in Thailand, where is a resource-limited setting, is covered by the National AIDS Program. Therefore, we aimed to investigate the different methods, using serum creatinine (SCr), calculated CrCl (CCrCl), and eGFR, for the monitoring of renal function among HIV-infected patients receiving TDF in routine HIV clinical care. Proportion, incidence rate, and risk factors for renal function declines will be determined using the different criteria.

Patients and Methods

Retrospective and prospective cohort studies were conducted among HIV-infected patients who attended the HIV clinic at Chonburi Hospital (an 825-bed tertiary care hospital), Thailand, between January 2007 and October 2009. Inclusion criteria were as follows (1) age ≥18 years, (2) received a normal dose of TDF for a minimum of 3 months, (3) had information on baseline weight and serum creatinine, and (4) had baseline eGFR >50 mL/min per 1.73 m². Exclusion criteria were (1) received concurrent indinavir (IDV) and other nephrotoxic medications and (2) did not have at least 1 follow-up visit at the HIV clinic after TDF initiation. Written information consent was obtained from all study participants. The study was reviewed and approved by the institute review board of Chonburi Hospital.

Baseline demographic information including baseline and follow-up laboratory investigations were retrieved and reviewed. The demographic data included gender, age, weight, height, body mass index (BMI), duration on ART before TDF initiation, any underlying condition that may be predisposed to renal function decline¹⁸ (eg, hypertension, diabetes mellitus, hepatitis C and B virus coinfection), concurrent nephrotoxic medications^18,19 (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], amphotericin B, trimethoprim-sulfamethoxazole, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside, acyclovir, and radiocontrast media), and duration of TDF treatment. Baseline laboratory parameters at TDF initiation included CD4 counts, HIV RNA, and serum creatinine. Follow-up parameters included body weight and serum creatinine at 3, 6, 9, 12, 18, 24, 30, and 36 month after TDF initiation. If these parameters were not available at the specific time points, a 4-week window period was acceptable.

Calculated creatinine clearance was calculated using the Cockcroft-Gault (C-G) formula.²⁰ Estimated GFR was calculated using the 4-variable Simplified Levey modification of diet in renal disease (MDRD) formula.²¹Study end point or outcome of interest definition, which was renal function decline, was defined by an increase in SCr by 1.5 times from the baseline or a 25% decrease in either CCrCl or eGFR from the baseline.²²

Mean (standard deviation [SD]), median (interquartile range [IQR]), and frequencies (%) were used to describe patients' characteristics. Incidence of renal function decline was calculated by dividing the number of cases with this outcome of interest by person-time at risk, which was the time from the date of TDF initiation to the date of the outcome, last follow-up visit, death, or the end of study period on December 31, 2009. Time from TDF initiation to renal function decline was analyzed using Kaplan-Meier estimates. Univariate logistic regression was used to determine the factors associated with the outcome of interest as described above. Variables that presented P < .20 were considered in a multivariate logistic regression model. Odds ratio (OR) and its 95% confidence interval (CI) were estimated. A P value < .05 was considered statistically significant. All statistical analyses were performed using the 16.0 version of SPSS program (SPSS Inc., Chicago, Illinois).

Results

A total of 356 HIV-infected patients were eligible for inclusion in the analysis. Median (IQR) age was 40 (35-45) years and 57% were males. Most patients (354 patients, 99%) were ART-experienced individuals at TDF initiation. Median (IQR) baseline body weight and BMI was 56 (50-65) kg and 19.6 (17.9-21.8) kg/m², respectively. Median (IQR) CD4 count was 379 (237-521) cells/mm³. Median (IQR) baseline renal function determined by SCr, CCrCl, and eGFR were 0.9 (0.8-1.0) mg/dL, 79.6 (69.4-94.6) mL/min, and 88 (76.6-100) mL/min per 1.73 m², respectively. Baseline characteristics and laboratory investigations of 356 patients are shown in Table 1.

Table 1.

Baseline Characteristics and Laboratory Investigations at Tenofovir Initiation of 356 Patients

Characteristics
Median (IQR) age, years	40 (35-45)
Male gender, n (%)	203 (57)
Median (IQR) body weight, kg	56 (50-65)
Median (IQR) body mass index, kg/m²	19.6 (17.9-21.8)
Underlying disease, n (%)	71 (19.9)
Hepatitis B and/or hepatitis C virus infection, n (%)	30 (8.4)
Hypertension, n (%)	25 (7.0)
Diabetes mellitus, n (%)	16 (4.5)
Median (IQR) CD4 counts, cells/mm³	379 (237-521)
Median (IQR) duration of antiretroviral therapy before TDF initiation, month	48 (24-72)
Antiretroviral therapy regimen
NNRTI-based regimen, n (%)	253 (71.1)
PI-based regimen, n (%)	103 (28.9)
Median (IQR) baseline SCr, mg/dL	0.9 (0.8-1)
Median (IQR) baseline CCrCl, mL/min	79.6 (69.4-94.6)
Median (IQR) baseline eGFR, mL/min per 1.73 m²	88 (77.6-100)

Abbreviations: CCrCl, calculated creatinine clearance; eGFR, estimated glomerular infiltration rate; IQR, interquartile range; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; SCr, serum creatinine; SD, standard deviation; TDF, tenofovir.

A median (IQR) duration of receiving TDF was 15.5 (8-21) months. At each follow-up visit, the number of patients with renal function decline detected by the different methods differed accordingly. At the 6th month after TDF initiation, 8 (2.3%), 15 (4.2%), and 18 (5.0%) patients had renal function decline defined by the SCr, CCrCl, and eGFR, respectively. At the 30th month, 19 (5.3%), 53 (14.9%), and 63 (17.7%) patients had renal function decline defined by the above criteria. There was a significant difference in the number of patients with renal function decline using SCr criteria compared to that using both CCrCl (P < .001) and eGFR criteria (P < .001). In contrast, there was no difference in the number of patients with renal function decline using CCrCl and eGFR criteria (P = .310). The cumulative number of patients with renal function decline by each method stratified by follow-up visit is shown in Figure 1.

Figure 1.

Cumulative number of patients with renal function decline defined by each method.

An incidence of renal function decline using the above criteria was 4.5, 12.5, and 14.6/100 person-year, respectively. Median (IQR) time to renal function decline was 8 (3-13.5), 11 (6-18), and 11 (6-19) months, respectively, when estimated from the total number of the patients. By Kaplan-Meier analysis, median time to renal function decline was 28 (95% CI 25-30) months for eGFR criteria and 31 (95% CI 28-34) months for CCrCl criteria. We could not determine the median time to renal function decline using SCr criteria because of a low number of patients with this outcome.

By multiple logistic regression, lower baseline BMI (OR 1.28 per 1 kg/m², 95% CI 1.05-1.57, P = .015), duration of ART before TDF initiation (OR 1.02 per month, 95% CI 1.00-1.03, P = .021), and lower baseline SCr (OR 0.01 per 0.1 mg/dL, 95% CI 0.00-0.07, P < .001) were statistically significantly associated with renal function decline defined by the SCr criteria. Only higher baseline CCrCl (OR 1.88 per 10 mL/min, 95% CI 1.52-2.32, P < .001) was statistically significantly associated with renal function decline defined by the CCrCl criteria. Lower baseline body weight (OR 1.13 per 5 kg., 95% CI 1.00-1.13, P = .032), lower baseline BMI (OR 1.32 per 1 kg/m², 95% CI 1.19-1.48, P = .015), higher baseline eGFR (OR 1.63 per 10 mL/min per 1.73 m², 95% CI 1.39-1.92, P < .001), and protease inhibitor-containing regimen (OR 2.28, 95% CI 1.17-4.44, P = .015) were statistically significantly associated with renal function decline defined by the eGFR criteria. Table 2 shows the associated factors for TDF-associated renal function decline defined by each criteria using multivariate logistic regression analysis.

Table 2.

Associated Factors for Tenofovir-Associated Renal Function Decline Using Serum Creatinine, Creatinine Clearance, and Glomerular Filtration Rate Criteria by Multivariate Logistic Regression Analysis

Variables	Renal Function Monitoring Method
SCr (N = 19)	CCrCl (N = 53)	eGFR (N = 63)
Odds Ratio (95% CI) P Value	Odds Ratio (95% CI) P Value	Odds Ratio (95% CI) P Value
Lower body weight, per 5 kg	–	–	1.13 (1.00–1.13) .032
Lower body mass index, per 1 kg/m²	1.28 (1.05–1.57) .015	–	1.32 (1.19–1.48) .015
Duration of antiretroviral therapy before TDF initiation, per month	1.02 (1.00–1.03) .021	–	–
Lower baseline SCr, per 0.1 mg/dL	0.01 (0.00–0.07) <.001	–	–
Higher baseline CrCl, per 10 mL/min	–	1.58 (1.34–1.88) <0.001	–
Higher baseline GFR, per 10 mL/min per 1.73 m²	–	–	1.63 (1.39–1.92) <.001
Protease inhibitor-containing regimen	–	–	2.28 (1.17–4.44) .015

Abbreviations: CCrCl, calculated creatinine clearance; CI, confidence interval; eGFR, estimated glomerular infiltration rate; SCr, serum creatinine; TDF, tenofovir.

Discussion

The present study is one of the first few studies evaluating the 3 different methods for renal function monitoring in HIV-infected patients receiving TDF in the routine HIV care clinic and in a resource-limited setting. The results of this study demonstrate a high proportion and incidence rate of TDF-associated renal function decline irrespective of the criteria. Significant change of SCr was detected in only 5.3%, in contrast to that of CCrCl (14.9%) and eGFR (17.7%). Our group and the others also have reported subtle changes in CCrCl or eGFR associated with TDF.^9,11,23 In addition, the recent systematic review and meta-analysis demonstrates that there was a significant renal function decline including acute kidney injury among individuals receiving TDF, compared with control participants.²⁴ Nevertheless, some groups have reported slight changes in renal function without clinically relevant renal disease.^17,25,26

The report on the TDF-associated nephrotoxicity is nonstandardized and is a consequence of creating confusion about the actual incidence including risk factors of this complication.²⁷ Risk of TDF-associated nephrotoxicity is low (approximately 1%) among populations in the clinical trials, which highly selected case with good condition, have appropriate TDF dosing, and vigilance in patient monitoring.²⁷ In contrast, some observational cohort studies suggest a higher risk. Rates of TDF-associated nephrotoxicity in retrospective cohort studies have been reported in general at approximately 2%.^28,29 We found a higher incidence of TDF-associated renal function decline among Thai HIV-infection, which ranged from approximately 5% to 18%, depending on the criteria. This may be explained by a lower body weight, experience to ART, and use of protease inhibitor in our population enrolled in the cohort. It is not surprising, given that patient populations are more heterogeneous and treatment is more complex in real-world situations. The variation in the results from study to study may be attributable to the difference in the methods and/or criteria of monitoring, study population, lack of standard definition, recognition, and/or reporting biases.

The differences between formulae are based on the relative emphasis of age and sex as well as the presence of weight in the C-G formula and race in the MDRD formula.²⁷ Despite the importance of accurate GFR estimation in HIV-infected individuals, available estimates have not been validated and most comparative studies have included white men with relatively well-preserved kidney function.¹⁴ We did not find a statistically significant difference in the proportion (14.9% vs 17.7%) and incidence rate (12.5 vs 14.6/100 person-year) of TDF-associated renal function decline when using CCrCl and eGFR. There was a study reporting that the C-G and 4-variable MDRD eGFR were highly correlated, but both underestimated the 24-hour urine CrCl in HIV-infected adults without chronic kidney disease.³⁰ However, in some reports, the MDRD formula is considered to be more accurate than the C-G formula, which may overestimate renal function.^21,31 Using MDRD formula may still have a high level of bias, depending on creatinine assay calibration, and low precision, with approximately 80% of eGFR in the range of 70% to 130% of the measured GFR value.³¹ In addition, the accuracy of the MDRD formula tends to decrease in the elderly and/or in patients with extremely low and high BMI when compared to the C-G formula.^32,33

Using SCr criteria is less sensitive for detecting renal function decline in this cohort. Renal function declines using SCr criteria were detected in the lowest proportion and incidence rate. The endogenous production of creatinine is primarily determined by muscle mass and dietary intake, which probably accounts for the variations in SCr levels observed among different age, geographic, ethnic, and racial groups.³⁴ Furthermore, a significant increase in SCr will be detected only when GFR should have decreased to approximately 60% of its normal level.³⁵

We also demonstrate risk factors associated with renal function decline. Some of these factors are described in the previous reports, for example body weight,^36,37 protease inhibitor-containing regimen,^19,38 and baseline renal function.²⁵ Low-body weight might lead to high TDF concentrations and increased risk of kidney impairment.³⁷ According to our findings in this study and the recently published article,⁹ we hypothesize that the 300 mg dosage of TDF may be too high for patients with lower body weight. Patients with lower body weight, for example, less than 60 kg, should receive a lower dose of TDF. Nevertheless, both pharmacological and clinical studies are needed to support this conjecture.

The reasons why high baseline renal function, for example, lower serum creatinine, lower CrCl, and higher GFR, is associated with renal function decline remain unclear. It could be possible that, for patients with low baseline of CrCl or GRF, it is more difficult to see renal function decrease.²⁵ Future study is needed to explore this association. Using the different methods for renal function monitoring as the dependent variable, the risk factors will be determined differently depending on the model. However, the effect of these factors on the dependent variable is in the same direction with high precision regardless of the method of renal function monitoring.

This cohort study is limited by its retrospective study design in some parts, and prospective controlled studies are warranted to confirm this observation. Furthermore, monitoring of renal function was determined at 3-month intervals as a part of routine patient follow-up visits at the HIV clinic. This may not represent the actual incidence including timing of TDF-associated renal function decline. In addition, other TDF-associated nephrotoxicities, such as tubular dysfunction, could not be determined because serum electrolyte and phosphate including urinary analysis are not routinely performed. Some patients have tubular dysfunction in the absence of the glomerular dysfunction.³⁹

In summary, our results show that both proportion and incidence rate of TDF-associated relevant renal function declines are high irrespective of the method of monitoring, although the different methods used for monitoring provided different results. Close monitoring of renal function is essential for prevention and early detection of renal function decline especially among patients who had risk factors. Monitoring renal function decline associated with the use of TDF by CCrCl using the C-G formula and eGFR using the MDRD formula is practical in routine HIV care, although it may have a concern of infrastructure, especially in resource-limited settings. We encourage health care providers to calculate, at least, either CCrCl or eGFR, not only SCr, for monitoring of renal function among HIV-infected patients receiving TDF in resource-limited settings. Further studies are needed to evaluate the methods for accurate renal function monitoring among HIV-infected patients.

Footnotes

Acknowledgments

The authors would like to thank Assistant Professor Somreuthai Watcharaviwat, Assistant Professor Suttiporn Pattarachayakul, and Wichai Suntimaleevorrakul for their suggestions. We also would like to thank the staff of anonymous clinic, Chonburi Hospital, for their enormous support, and Professor Emeritus Roger Bowen, Department of English, University of Arizona, for reviewing the manuscript.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Monitoring of Renal Function among HIV-Infected Patients Receiving Tenofovir in a Resource-Limited Setting

Abstract

Keywords

Introduction

Patients and Methods

Results

Discussion

Footnotes

Acknowledgments

References