Renal safety of tenofovir in HIV-infected patients who switch from stavudine or zidovudine to tenofovir

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1 Original Article Vol. 29 No. 3 Renal safety of tenofovir:- Wiwattanathum P & Sungkanuparph S. 113 Renal safety of tenofovir in HIV-infected patients who switch from stavudine or zidovudine to tenofovir Punlop Wiwattanathum, M.D., Somnuek Sungkanuparph, M.D. ABSTRACT Background: Effectiveness of antiretroviral therapy (ART) results in better survival and quality of life in HIV-infected patients. However, adverse events from the use of antiretroviral drugs can limit this success. Tenofovir (TDF) has been increasingly used in Thailand particularly as a substitution for stavudine (d4t) and zidovudine (AZT). Renal safety of tenofovir use in HIV-infected patients who switch from d4t or AZT to TDF has not been well established. Methods: A prospective cohort study was conducted in HIV-infected patients who switched from d4t or AZT to TDF, as a component of ART regimen, between January and December 2011 at Ramathibodi Hospital, Mahidol University. Patients serum creatinine (Cr), phosphate, uric acid, and urine protein/cr ratio were measured at the time of switching to TDF and at 3 months and 6 months after switching. Creatinine clearance (CrCl) was calculated using MDRD, Cockroft-Gault and CKD-epi formula. Result: A total of 40 patients were studied. Median (IQR) age was 45.7 ( ) years and 68% were male. Median (IQR) body weight was 58.0 ( ) kgs. Of the 40 patients, 3 (8%) had chronic kidney disease with estimated GFR ml/min. Median (IQR) CD 4 cell count was 414 ( ) cell/mm 3. Regarding ART regimens, NRTIs back bones were TDF/lamivudine (63%) and TDF/ emtricitabine (37%); combined with NNRTIs (90%) or PIs (10%). The mean ± SD baseline Cr, CrCl, serum phosphate, serum uric acid and urine protein/cr ratio were 0.90 ± 0.21 mg/dl, 87.1 ± 22.3 ml/min, 3.47 ± 0.50 mg/dl, 5.24 ± 2.10 mg/dl and 0.16 ± 0.12, respectively. After 6 months of TDF use, mean ± SD Cr, CrCl, serum phosphate, serum uric acid and urine protein/cr ratio were 0.89 ± 0.30 mg/dl, 89.2 ± 18.1 ml/min, 3.38 ± 0.57 mg/dl, 5.09 ± 2.02 mg/dl and These values were not significantly different from baseline (p>0.05). Calculated CrCl using other formula gave similar results. The mean change of CrCl using MDRD, Cockcroft-Gault and CKD-Epi equation were -2.08, and ml/min, respectively (p>0.05). Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. Reprint request: Somnuek Sungkanuparph, M.D., Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. Keywords: HIV, kidney, tenofovir, stavudine, zidovudine 113

2 114 J INFECT DIS ANTIMICROB AGENTS Sep.-Dec Conclusion: No significant change in renal function, serum phosphate, serum uric and urine protein/ Cr ratio in HIV-infected patients who switch from d4t or AZT to TDF. TDF is safe in short term use. Although we did not detect significant change in renal function in this study, screening of renal function before TDF use and monitoring during TDF use are suggested for long term TDF use. (J Infect Dis Antimicrob Agents 2012;29: ) INTRODUCTION In the current use of antiretroviral treatment, the prevalence of renal impairment in HIV-infected patients is about 5-10%. 1,2 Renal impairment can be caused by both HIV-related and non-hiv-related causes. Although antiretroviral drugs improve the course of HIV infection in terms of reducing morbidity and mortality, they may increase the risk of comorbid chronic kidney disease (CKD) or nephrotoxicity. 3,4 In late 2009, the World Health Organization (WHO) issued statements suggesting that developing countries phase out the use of stavudine (d4t) in HIVinfected patients due to its adverse effects. 5 Other antiretroviral drugs, such as zidovudine (AZT) and tenofovir (TDF) with fewer adverse effects are suggested to use and replace d4t. 6,7 According to the recommendations of WHO together with the new Thai National Guidelines for HIV treatment, 5,8 tenofovir will be increasingly used in both first-line antiretroviral therapy and switching from d4t or AZT. Tenofovir Disoproxil Fumarate (TDF, Viread ) was approved by US FDA in the year 2001 and has been available in Thailand since TDF is classified in the group of nucleotide reverse transcriptase inhibitors (NtRTI) and is indicated for the combination with other drugs to treat patients infected with HIV. The drug is changed in the body to tenofovir diphosphate, a substance believed to be the least mitochondrial toxic when compared to other antiretroviral drugs. 9 This drug can be used together with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs). The recommended dosage of TDF is 300 mg once a day because the drug has a long intracellular half-life. Common adverse drug events include diarrhea, nausea, vomiting, abdominal pain and renal insufficiency. 10 TDF can be used for the treatment of drug resistance HIV. Thus, this drug is commonly used in patients with HIV drug resistance or adverse drug events due to other NRTIs. In addition, the drug has an activity against the hepatitis B virus (HBV). Therefore, TDF is a very important antiretroviral drug used for the treatment of HIV/HBV co-infection. 8 Previous studies have shown that renal insufficiency can be found in patients infected with HIV and receiving TDF. However, the information of this adverse event in patients with HIV infection in Thailand, particularly in patients who switch from other NRTIs to TDF, has not been well established. This study aimed to prospectively evaluate the renal function among HIV-infected patients who switch from d4t or AZT to TDF. MATERIALS AND METHODS Patient population and study design A prospective cohort study was conducted in HIV-infected patients who had been cared for between January 2011 and December 2011 at Ramathibodi Hospital, Mahidol University. Inclusion criteria included HIV-infected patients who 1) had an age of > 15 years old, 2) switched from d4t or AZT

3 Vol. 29 No. 3 Renal safety of tenofovir:- Wiwattanathum P & Sungkanuparph S. 115 to TDF. Exclusion criteria included patients who were pregnant or took other medications that could cause renal insufficiency. The study was approved by the local ethics committee. Data collection and calculation Clinical data including demographics, body weight, underlying diseases, previous opportunistic infection, previous antiretroviral regimens, and causes of changing antiretroviral drugs were reviewed from medical records and collected. The results of laboratory investigations including blood chemistries, CD 4 cell count, HIV viral load, and urinalysis were retrieved from medical records. At the time of switching to TDF, and at 3 and 6 months after switching to TDF, patients serum was measured for creatinine (Cr), electrolytes, glucose, phosphate, and uric acid; urine was measured for glucose, protein, Cr, phosphate, and uric acid. Estimated creatinine clearance (Crcl) was calculated using Modification of Diet in Renal Disease (MDRD) equation, 11 i.e. CrCl (ml/min) = 186 x serum creatinine x age For females, the formula requires multiplication by CrCl was also calculated with Cockcroft-Gault equation [{(140 - age) x weight/(72 x serum creatinine)} for male; {(140 - age) x weight/(72 x serum creatinine)}x 0.85 for female] and CKD-Epi equation 12 [GFR = 141 X min(scr/k,1) a X max(scr/k,1) x Age x (if female) x (if black)]. Statistical analysis Median (interquartile range, IQR) and frequencies (percentage) were used to show the patients characteristics. Mean (± SD) was used to show laboratory investigation results. Paired t-test was used to compare the continuous variables between two different time points in the same group. One way 115 ANOVA was used to compare mean change of CrCl between three methods of CrCl calculation (MDRD equation, Cockcroft-Gault equation and CKD-Epi equation). Statistical significance was defined as p < Statistical analysis was performed using SPSS program version RESULTS We studied 40 patients with a median (IQR) age of 45.7 ( ) years and 67.5 percent were male. Median (IQR) body weight was 58.0 ( ) kg. Three of 40 patients had CKD, estimated GFR was 44 ml/min in one patient and was 59 ml/min in the other two patients. Median (IQR) CD 4 cell count was 414 ( ) cell/mm 3. All of patients had undetectable HIV RNA (< 50 copies/ml). Table 1 shows the clinical characteristics of the study patients. Antiretroviral agents other than TDF used in the study were listed in Table 2. Reasons for using TDF in 40 study patients included lipodystrophy from d4t and/or AZT (97.5%), and HBV co-infection (2.5%). The mean ± SD baseline creatinine (Cr) and creatinine clearance (CrCl) were 0.90 ± 0.21 mg/dl and 87.1 ± 22.3 ml/min, respectively. The mean ± SD baseline serum phosphate, serum uric and urine protein/ Cr ratio were 3.47 ± 0.50 mg/dl, 5.24 ± 2.10 mg/dl and 0.16 ± 0.12, respectively. The results of all laboratory investigations at the time of switching to TDF and at 3 and 6 months after switching were summarized in Table 3. After 6 months of switching to TDF, mean ± SD Cr, CrCl serum phosphate, serum uric and urine protein/ Cr ratio were 0.89 ± 0.30 mg/dl, 89.2 ± 18.1 ml/min, 3.38 ± 0.57 mg/dl, 5.09 ± 2.02 mg/dl and 0.21 ± Serum Cr, CrCl, serum phosphate, serum uric and urine protein/cr ratio were not significantly different from baseline (p > 0.05, Table 3). There was no difference of CrCl change between using MDRD equation,

4 116 J INFECT DIS ANTIMICROB AGENTS Sep.-Dec Table 1. Baseline characteristics of 40 patients switching to TDF. Characteristics Values Gender, number (%) Male 27 (67.5) Female 13 (32.5) Age, years, median (IQR) 45.7 ( ) Body weight, kgs, median (IQR) 58.0 ( ) Underlying diseases, number (%) Diabetes mellitus 2 (5) Hypertension 5 (12.5) Chronic kidney disease 3 (7.5) Dyslipidemia 4 (10) COPD 1 (2.5) Hemophilia A 1 (2.5) Previous opportunistic infections, number (%) Tuberculosis 15 (37.5) Pneumocystis pneumonia 3 (7.5) Cryptococcosis 2 (5.0) Candidiasis 2 (5.0) Toxoplasmosis 1 (2.5) Penicillosis 1 (2.5) Herpes zoster 2 (5.0) CD 4 cell counts, cells/mm 3, median (IQR) 414 ( ) CD 4 percent, %, median (IQR) 18.5 ( ) Cockcroft-Gault equation, and CKD-Epi equation. The mean CrCl changes of three methods were -2.08, and ml/min, respectively (p > 0.05). During follow up at 3 and 6 months after switching to TDF, urinalysis of all patients showed neither urinary cast nor significant WBC. DISCUSSION The results from the present study have demonstrated that no change in renal function, serum phosphate, serum uric and urine protein/cr ratio within 6 months after switching form d4t or AZT to TDF. These findings of renal safety encourage the switching of other NRTIs to TDF. Comparing with previous studies, 13,14 our study has found no deterioration of renal function while previous studies addressed that the use of TDF was associated with a greater decline in renal function. However, the declines were modest and did not lead to greater rates of discontinuation of therapy. The difference of these findings may be explained by the different duration of study, as well as other factors such as age, comorbidities, antiretroviral regimens, and baseline renal function. 13,14 A retrospective study in Thailand had reported 1.4% of patients developed acute

5 Vol. 29 No. 3 Renal safety of tenofovir:- Wiwattanathum P & Sungkanuparph S. 117 Table 2. Antiretroviral agents used with TDF in 40 patients switching to TDF. Antiretroviral agents Number (%) Regimens NNRTI-based regimens Navirapine 22 (55.0) Efavirenz 14 (35.0) PI-based regimens Lopinavir/ritonavir 3 (7.5) Atazanavir/ritonavir 1 (2.5) NRTI back bones Lamivudine/Tenofovir 25 (62.5) Emtricitabine/Tenofovir 15 (37.5) Table 3. Baseline and follow-up laboratory investigations of 40 patients switching to TDF. Variables Values (mean ± SD) Difference* P-value Baseline 3 month 6 month Creatinine, mg/dl 0.90 ± ± ± ± Creatinine clearance, ml/min A ± ± ± ± Creatinine clearance, ml/min B ± ± ± ± Creatinine clearance, ml/min C ± ± ± ± Serum sodium, mg/dl ± ± ± ± Serum potassium, mg/dl 4.11 ± ± ± ± Serum chloride ± ± ± ± Serum bicarbonate, mg/dl ± ± ± ± Serum glucose, mg/dl ± ± ± ± Serum phosphate, mg/dl 3.47 ± ± ± ± Serum uric, mg/dl 5.24 ± ± ± ± Urine glucose, mg/dl ± ± ± ± Urine phosphate, mg/dl ± ± ± ± FE phosphate** 0.11 ± ± ± ± Urine uric, mg/dl ± ± ± ± FE uric** 0.97 ± ± ± ± Urine protein/urine creatinine 0.16 ± ± ± ± *Difference = compared results between at baseline and 6 months after switching to TDF of each variables **FE phosphate = Fractional excretion of phosphate, FE uric acid = Fractional excretion of uric acid Creatinine clearance calculated using A = MDRD equation; B = Cockcroft-Gault equation; C = CKD-Epi equation 117

6 118 J INFECT DIS ANTIMICROB AGENTS Sep.-Dec renal failure at 6 months. 15 However, this previous study had higher proportion of patients receiving PIs with TDF, when compared to our study. Another Thai study had demonstrated that using PIs with TDF increases the risk of renal impairment with an odd ratio of In addition, excluding patients receiving other medications that can cause renal insufficiency in this study also explains the lower rate of patients with renal insufficiency in this study. Using concomitant nephrotoxic drug was also proven to be associated with increased renal insufficiency. 16 In term of serum phosphate, serum uric acid and urine protein/cr ratio, previous study found no change from baseline as well. 13,14 The limitations of present study included small sample size and relatively short time for monitoring of renal function. However, this prospective study in reallife setting can provide relevant information in the setting of switching from d4t or AZT to TDF. In conclusion, TDF is commonly used for substitution of d4t or AZT in Thailand and switching is mainly as a result of adverse effects of d4t or AZT rather than treatment failure. Switching to TDF is optimal and has renal safety particularly in short term based on this study. Clinician should screen whether the patient is vulnerable to the adverse effects on the kidney or not. Early detection of risk factors for chronic kidney disease and monitoring of renal function while treating patients with TDF should be advocated for improvement of the patients quality of life. References 1. Fernando SK, Finkelstein FO, Moore BA, Weissman S. Prevalence of chronic kidney disease in an urban HIV infected population. Am J Med Sci 2008;335: Crum-Cianflone N, Ganesan A, Teneza-Mora N, et al. Prevalence and factors associated with renal dysfunction among HIV-infected patients. AIDS Patient Care STDS 2010;24: Szczech LA, Gupta SK, Habash R, et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int 2004;66: Campbell LJ, Ibrahim F, Fisher M, Holt SG, Hendry BM, Post FA. Spectrum of chronic kidney disease in HIV-infected patients. HIV Med 2009;10: World Health Organization. Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents [Internet]. November 2009 [cited 2012 Feb 29]. Available from: rapid_advice_art.pdf 6. Bender MA, Kumarasamy N, Mayer KH, et al. Costeffectiveness of tenofovir as first-line antiretroviral therapy in India. Clin Infect Dis 2010;50: Walensky RP, Wood R, Ciaranello AL, et al. Scaling up the 2010 World Health Organization HIV Treatment Guidelines in resource-limited settings: a model-based analysis. PLoS Med 2010;7:e Sungkanuparph S, Techasathit W, Utaipiboon C, et al. Thai national guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents Asian Biomed 2010;4: Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D Agati VD, Markowitz GS. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int 2010;78: Fernandez-Fernandez B, Montoya-Ferrer A, Sanz AB, et al. Tenofovir nephrotoxicity: 2011 update. AIDS Res Treat 2011;2011: Levey AS, Coresh J, Greene T, et al. Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem 2007;53:

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