 |
|
|
| |
8 Studies at IAC Bangkok on Tenofovir Renal Safety
|
| |
| |
|
|
| |
| |
 |
|
| |
| |
Reported by Jules Levin
My take on these studies is if you have underlying potential for kidney dysfunction, andyou may not know if you do, it may surface on TDF so you should be closely monitoring your renal function.
Renal dysfunction with tenofovir DF containing HAART regimens is not observed more frequently: a cohort and case control study
R Jones, J Stebbing, M Nelson, G Moyle, M Bower, S Mandalia, B G Gazzard
Chelsea & Westminster Hospital , London, United Kingdom
Background: Tenofovir disoproxil fumarate (TDF) is the first nucleotide reverse transcriptase inhibitor approved for the treatment of HIV infection. Despite recent case reports, there are no data on the overall incidence and risk of renal dysfunction in individuals receiving tenofovir DF .
Methods: Data from the Chelsea and Westminster cohort was analysed to reveal HIV positive individuals with a creatinine greater than 120 µmol/l at any time and classify them according to anti-retroviral exposure and time exposed. A matched case control study was performed comprising patients who had received tenofovir DF and subsequently developed a creatinine greater than 120 µmol/l, against controls who had been treated with tenofovir DF and not experienced a creatinine elevation.
Results: From 4,183 HIV positive patients, 1,175 were identified as having a recorded creatinine >120 µmol/l. Comparison of antiretroviral naïve patients, and patients exposed to tenofovir DF and non-tenofovir DF containing regimes revealed a lower rate ratio and probability of developing a creatinine > 120 µmol/l in patients exposed to tenofovir DF (rate ratio versus no anti-retrovirals 0.22, 95% CI 0.07 to 0.69, p < 0.001) with no significant difference between HAART regimens, corrected for duration of exposure. Of the 1,058 individuals who were exposed tenofovir DF, 84 patients (8%) experienced a creatinine > 120 µmol/l subsequent to exposure. An alternative aetiology of renal dysfunction was found in 75 (90%) of these individuals.
Conclusion: This study demonstrates that renal failure associated with tenofovir DF is not more common than with other anti-retroviral drugs. In 1,058 individuals exposed to tenofovir DF, a maximum of 9 patients (0.01%) developed an increased creatinine without other obvious cause. The majority of patients in this study had concurrent reasons for renal dysfunction, thus it is not possible to attribute creatinine elevation to tenofovir exposure alone. Overall, receiving HAART is associated with improved renal function, as measured by creatinine levels, compared to not receiving HAART.
Incidence of Tenofovir-related nephrotoxicity in a large outpatient cohort
E Jaegel-Guedes1, E Wolf2, N Ruemmelein1, N Postel1, C Koegl2, A Buchberger1, J Wandel2, S Weisser2, H Jaeger3
1Private Practice Dr. Jaegel-Guedes/Dr. Jaeger, Munich, Germany; 2MUC Research GmbH, Munich, Germany; 3KIS - Curatorium for Immunedeficiency, Munich, Germany
Background: To date, clinical studies with tenofovir (TDF), a renally eliminated nucleotide analogue, have not observed severe nephrotoxicity so far. However, single case reports of renal toxicity outside of clinical trials have raised concerns about the respective risk.
Methods: Retrospective follow-up study of an outpatient HIV cohort being started on TDF between 8/2001 and 5/2003. Patient (pt) files were monitored for abnormalities in renal function such as serum creatinine and clinical events. Creatinine clearance was estimated using the Cockroft-Gault formula.
Results: So far, observation time in 206 pts (16% female) is 227 patient years (PY) with a median of 12.5 months. At baseline (BL), one pt had a history of renal impairment; 28% of pts were on additional potentially nephrotoxic drugs, 42% started with respective drugs during follow-up. BL creatinine levels were all within normal ranges (<1.3 mg/dl) with a median of 0.74 mg/dl, creatinine clearance was slightly impaired in 12% of pts with a level between 60-89 ml/min.
Overall, median increase in creatinine was 0.11 mg/ml (last observation carried forward) with a WHO grade 1 increase of >+0.5 mg/dl in 2 pts. Two further pts experienced acute renal failure after 2 and 5 months. In one case - with a BL creatinine clearance of 89 ml/min - renal failure was related to the concomitant use of nephrotoxic drugs (such as vancomycin, NSAID and acyclovir). The 2nd patient had a history of renal failure associated with Burkitt's lymphoma and suffered from progressive disease while on chemotherapy.
Conclusions: The overall risk of TDF-related nephrotoxicity was low in our cohort. In pts with normal baseline renal function, only 1% experienced creatinine increases of WHO grade 1. Overall incidence of renal failure was < 1/100 PY. Renal failure occurred in 2 out of 25 pts with pre-existing renal dysfunction. Relationship with TDF could not be excluded in these pts, but other cofactors were more likely to contribute to renal failure.
Effect of Tenofovir on renal function in a "real world" clinic setting
M A Horberg1, D B Klein2, J Yu3, K Sinn2, J Yu1
1Kaiser-Santa Clara, Santa Clara, CA, United States; 2Kaiser-Hayward, Hayward, CA, United States; 3Kaiser-Santa Clara, Santa Clara, CA, United States
Background:Tenofovir (TFV) is now widely used in HIV therapy, for both naïve and experienced patients. Though not described in initial studies, reports now suggest elevated creatinine with TFV use. We reviewed our data in this ïreal worldï cohort of patients to assess the effect of TFV on renal function.
Methods:Retrospective review of all patients on TFV for HAART at 5 medical centers in Kaiser-Permanente Northern California. Baseline creatinine (Cr), proteinuria, CD4, and viral load (log10--Chiron bDNA v.3) (VL) were noted, as were levels at 3, 6, and 12 months (when available) for all of these parameters. ∆Cr, ∆CD4, and ∆ VL were determined and T-test for statistical significance was employed.
Results: 199 patients were started on TFV--168 male, 31 female. 25 ART naïve, 124 exp., and 52 BLQ at start. 19 had prior renal disease, 20 had diabetes mellitus. 4 patients expired while on therapy. Results as below:
| Creatinine Median/Mean (Count) | Proteinuria | | Baseline | 0.8/0.9 (197) | 25 (169) | | 3 Month | 0.9/0.9 (182) | 15 (144) | | 6 Month | 0.9/1.0* (163) | 15 (124) | | 12 Month | 0.9/1.0* (95) | 7 (62) |
*--statistically significant vs. baseline (p<.05)
∆Cr was significant compared to baseline (p=.03 at 6 mo. and at 12 mo.). 15 patients developed proteinuria over the course of the 6 months, but none was greater than 100mg%. While ∆VL had a p <.0001 at 3, 6, and 12mo., ∆CD4 was +70 3mo. (p=.03), +45 6mo. (p=.13), and +38 12 mo. (p=.31) (as treated) and no difference for naïve/experienced pts.
Conclusions:While potent viral control, TFV did increase Cr in this real world clinical cohort. Implications for future renal insufficiency in this population must be considered. Few patients developed proteinuria. No statistically significant increase in CD4 at >3 months was appreciated.
Tenofovir is associated with mild renal dysfunction
S Mauss, F Berger, H Carls, G Schmutz
Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
Background: Tenofovir (TDF) has not shown nephrotoxic effects in clinical trials (Cheng 9th EACS 2003). However anecdotal data reported renal failure in patients (pts) on TDF.
Methods: A cross-sectional study was performed to in HIV pts treated with or without TDF. Creatinine, cystatin C, and electrolytes were measured in serum and in urine collected over 24-hours. Renal clearance was calculated on the basis of cystatin clearance (normal >80 ml/min) which is more sensitive than creatinine. To differentiate tubular from glomerular origin of proteinuria (>130 mg/d) a DISC-electrophoresis was done. Diabetes mellitus, hypertension, liver cirrhosis or known renal disease were exclusion criteria. For statistical analysis a 2-way analysis of variance including interactions was performed.
Results: 188 pts were enrolled. 24 pts met the exclusion criteria. Pts on TDF (n=74) showed a lower mean cystatin clearance (87±21 ml/min) compared to pts never treated with TDF (n=84) (96±20 ml/min) (p<0.01). 28 pts on TDF (38%) had a decreased cystatin clearance compared to 21 pts never treated with TDF (25%) (p=0.08). In addition pts on TDF had a higher mean protein content in urine (118±114 mg/d vs. 96±58 mg/d, p<0.05). In total 26 pts on TDF (35%) vs. 15 control pts (18%) had proteinuria >130 mg/d characterised by a tubular pattern with or without mild glomerular damage (p<0.02). No patient had a nephrotic or fanconi-like syndrome. No differences in electrolytes and creatinine were observed. In multivariate analysis no association was found between renal function or proteinuria and the time on all antiretrovirals, time on tenofovir or prior use of indinavir. In 3 pts proteinuria was completely reversible after discontinuation of TDF.
Conclusion: TDF is associated with mild renal dysfunction when measured with sensitive methods. This may render the kidney more vulnerable to concomitant treatment with nephrotoxic drugs. A detailed assessment of renal function should be included in the future design of trials using TDF.
Three-year analysis of the renal safety of tenofovir DF (TDF) versus stavudine (d4T) when used in combination with lamivudine (3TC) and efavirenz (EFV) in antiretroviral-naïve patients
S Staszewski1, J E Gallant2, A L Pozniak3, K Yale4, B Lu4, J Enejosa4, A K Cheng4
1University Hospital, J.W. Goethe-Universitat, Frankfurt, Germany; 2Johns Hopkins Univ. School of Medicine, Baltimore, MD, United States; 3Chelsea and Westminster Hosp., London, United Kingdom; 4Gilead Sciences, Foster City, CA, United States
Background: Sporadic cases of renal dysfunction attributed to TDF have been reported. An assessment of the long-term renal safety of TDF in study 903 was performed.
Methods: Study 903 was a Phase III, 144-week, multicenter, randomized, double-blind, active-controlled trial in ARV-naïve patients with HIV-1 RNA >5,000 copies/mL and any CD4 count. Patients were randomized to receive either TDF or d4T plus 3TC and EFV. Baseline serum creatinine was <1.5 mg/dL, serum phosphorus >= 2.2 mg/dL and calculated creatinine clearance was >=60 mL/min. Baseline demographics were equivalent.
Results: No significant differences in renal parameters were observed between TDF and d4T arms. None of the patients developed serum creatinine >2.0 mg/dL after week 48. No patient discontinued therapy due to renal toxicity in the TDF arm.
| Parameters | TDF+3TC+EFV | d4T+3TC+EFV | | N=296 | (n=296) | | Serum Creatinine >2.0 mg/dL | <1% (2) | <1 % (2) | | Serum Phosphorus <2.0 mg/dL | 3% (10) | 3% (8) | | Proteinuria (>30mg/dL) | 18% (54) | 23% (69) | | Glucosuria (>=250 mg/dL) | 3% (8) | 3% (9) | | Baseline Calculated Creatinine Clearance (ml/min)* | 122 | 125 | | Mean Change from Baseline in Calculated Creatinine Clearance (ml/min)* | +1 | +7 | | Fanconi's Syndrome | 0 | 0 |
*Using Cockcroft-Gault Equation
Conclusions: This three-year analysis demonstrates comparable renal safety between tenofovir DF and d4T. Neither proximal renal tubular dysfunction nor Fanconi's syndrome were seen through 144 weeks.
Rare occurrence of renal toxicity when retrospectively evaluating the use of Tenofovir DF in 2 clinical practices
J D Scott1, P R Wolfe2, J Quiros1, E Behrooznia1, B Guyer3, R K Bolan4
1Western University, Pomona, United States; 2Pacific Oaks Research, Beverly Hills, United States; 3Gilead Sciences, Foster City, United States; 4Jeffrey Goodman Clinic, Los Angeles, United States
Background: Tenofovir (TDF) was approved for treatment of HIV-1 in 2001. Pre-approval studies did not show any cases of renal toxicity (RT). A related compound, adefovir (ADF), was shown to cause proximal renal tubulopathy in HIV patients (pts) at daily doses of 120 mg and 60 mg. ADF has since been approved by the FDA for treatment of hepatitis-B infection at lower doses. Recent case reports of RT in pts taking TDF prompted this review.
Methods: We reviewed 447 charts of pts on TDF for at least 12 weeks from two large, urban, HIV clinics.
Results: All pts had baseline serum creatinine (SCr) values available and 434 (97%) were normal (<=1.5 mg/dL). Three pts (all male, two Caucasian, one African American) had Grade 1 RT within 24 wks. Three pts (all male, one Caucasian, one Asian, one Hispanic) had Grade 2 RT within 24wks. There were no Grade 3 or 4 increases in SCr noted within 24 wks of starting TDF. Two pts with Grade 1 RT had a concurrent opportunistic infection restricting fluid intake. In each of the three pts with Grade 2 RT, other medical events coincided with the increase in SCr: lactic acidosis (LA), pancreatitis, and indinavir-induced kidney stones. Six pts with baseline SCr >1.5 mg/dL had their SCr decrease and five remained stable. One pt progressed to Grade 2 due to LA, as noted above. Another had Grade 2 RT at baseline due to HIV nephropathy, but his SCr improved while on TDF.
Conclusions: Development of Grade 1 & 2 RT was rare (1.3%) in patients receiving TDF at these two clinics. Although no clinical nephrotoxicity was observed, continued observation of renal function is warranted in pts predisposed to RT.
Lack of systemic or renal drug interactions of tenofovir DF with adefovir dipivoxil or ribavirin
B P Kearney, J Sayre, J Shah, G Currie, A Cheng
Gilead Sciences, Foster City, CA, United States
Background: Tenofovir DF (TDF) is a nucleotide analogue HIV RT inhibitor with activity against hepatitis B virus (HBV). Co-infection with HBV and/or C virus is frequent in patients with HIV. Therefore, the drug interaction (DI) potential of TDF with agents used to treat HBV (adefovir dipivoxil, ADV) or HCV (ribavirin, RBV) was studied. In addition, the renal clearance of adefovir (ADF) and tenofovir (TFV) were evaluated to assess potential for renal/tubular secretion interactions.
Methods: Two PK studies were conducted. The single dose PK of ADV (n = 22) and RBV (n = 22) were studied following single doses given alone and with multiple doses of TDF. TFV PK were also evaluated following single doses of ADV or RBV. Study drugs were administered in the AM with blood/ urine sampling over 24 to 72 hours. Drug concentrations were determined using LC/MS/MS and PK parameters calculated by noncompartmental methods. PK equivalence was defined as a 90% confidence interval for the geometric mean ratio between 80 to 125% for Cmax and AUC. Renal clearance was compared using the Wilcoxon Signed Rank test.
Results: ADF and RBV were each equivalent when dosed alone or with TDF. TFV PK were also unaffected by ADV or RBV. TFV and ADF renal clearances were unchanged by TDF and ADV co administration. In both studies adverse events (AE) were generally mild.
--------------------------
Metabolic and renal profile before and after tenofovir DF
B Roca, C Gisbert, B Cabestany, A P Perez, J M Ventura
Hospital General, Castellon, Spain
Background: Metabolic side effects are common with several anti-HIV drugs. Tenofovir disoproxil fumarate (TDF), a non-nucleotide reverse-transcriptase inhibitor, seems to be free of significant toxicity of that kind, although data are scant. Renal toxicity of TDF seems also uncommon, but more data on that is also needed. We assess patients' metabolic and renal profile before and after including TDF in their anti-HIV treatments.
Method: In a cohort of outpatients, we assess blood analysis four months before switching to TDF regimens (month -4), just before switching (month 0), four months afterwards (month +4), and eight months afterwards (month +8). All treatments are among those recommended by guidelines, and changes in drugs are made because of side effects or simplification of regimens. Patients with protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) switch in their treatments are excluded.
Results: A total of 23 patients are included. Mean ± SD of age is 38 ± 4 years; 15 (65 %) are male; 13 (56 %) are drug users; 13 (56 %) are hepatitis C virus co-infected; regimens include PI in 8 patients (35 %) and NNRTI in 15 patients (65 %). Table shows the results of blood analysis (mg/dl, mean ± SD).
| Month | -4 | 0 | +4 | +8 | P | | Glucose | 104 ± 18 | 108 ± 43 | 103 ± 15 | 96 ± 21 | .015 | | Uric acid | 5.1 ± 1.6 | 4.9 ± 1.8 | 5.2 ± 1.4 | 5.3 ± 1.9 | .889 | | Total cholesterol | 188 ± 43 | 197 ± 49 | 178 ± 40 | 173 ± 31 | .002 | | HDL-cholesterol | 46 ± 12 | 47 ± 15 | 41 ± 11 | 46 ± 12 | .430 | | LDL-cholesterol | 87 ± 35 | 84 ± 38 | 74 ± 34 | 75 ± 36 | .254 | | Triglyceride | 239 ± 198 | 267 ± 241 | 264 ± 302 | 211 ± 134 | .553 | | BUN | 14 ± 4 | 13 ± 4 | 14 ± 4 | 15 ± 4 | .217 | | Creatinine | .9 ± .1 | .9 ± .2 | .9 ± .2 | .9 ± .2 | .772 |
Conclusion: TDF has a favorable short-term lipid and renal profile. A reduction in total cholesterol and glucose is observed in our cohort.
|
| |
|
|
|
|
|
