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Tenofovir Associated Kidney Dysfunction: The Controversy Continue
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Written for NATAP by Judith Aberg, MD, Bellevue Hospital, New York University
Medical Center
13th CROI, Feb 5-8, 2006, Denver
Dr Aberg ".....Although 10,343 patients enrolled in the expanded access program, follow up data was only available for 1699. Nevertheless, the review of this data was consistent with others. It is an uncommon event. TDF is associated with kidney disease in those given other drugs that adversely affect the kidney and advanced HIV disease. Much more work is needed to precisely understand who is at risk of developing kidney disease and to assure all measures are taken to avoid kidney toxicity....."
(Ed note from Jules: if taking tenofovir it is important to visit physician regularly every few months to monitor kidney function by checking laboratory values; there are risk factors for kidney dysfunction and they include diabetes & hypertension, and being African-American. It is not uncommon for HIV+ individuals to have risk factors for kidney dysfunction.
Last year I wrote a review on this same subject and spent considerable time discussing how the kidney functions and how one estimates the creatinine clearance in addition to discussing the presentations at the 2005 CROI. I refer readers back to my previous review rather than discussing how best to estimate how well the kidney works. At this 2006 CROI, Drs Samir Gupta and Judith Currier led the poster discussion on this topic, which became quite controversial with lots of on-going debates afterwards. I thought they both did an excellent job highlighting what it is we already knew and the incremental knowledge we gained by the data presented at this meeting.
Previous retrospective studies have suggested that tenofovir may be associated with kidney dysfunction in settings of pre-existing kidney disease (Ed note from Jules: when a patient alreadty has pre-existing kidney disease or dysfunction), concurrent use of nephrotoxic medications, lower body weight, lower CD4+ T-cell counts and possibly certain HIV drugs such as ritonavir boosted protease inhibitors and/or ddI. To date, we have not seen that prior adefovir use (a drug similar to tenofovir that is used to treat hepatitis B infection and known to have kidney toxicity), duration of tenofovir use, race or sex are associated with tenofovir associated kidney dysfunction.
There was really nothing new that was presented that changed my thoughts or knowledge about tenofovir associated kidney dysfunction except to say that I think we all agree that there is the potential for tenofovir to worsen kidney function in certain settings such as those mentioned above. Gilead scientists are working on defining the mechanism. Several potentials mechanisms were discussed during the open microphone session but it really is premature to attribute kidney toxicity to a certain receptor, transport system or efflux pump at this time. It is also premature to throw away a very potent medication used to treat HIV because of a very low risk of kidney toxicity. All of these drugs have side effects and we need to acknowledge what they are and learn how best to use them. Mistakes were made early on as we did not know that we needed to modify (decrease) the dose of tenofovir in patients with pre-existing kidney disease and we did not know some of the drug interactions. To date, there is no evidence that anyone with normal kidney function who is not taking another potentially toxic drug to the kidney and does not have advanced HIV disease has developed tenofovir associated kidney disease that is clinically significant. We do see that patients' serum creatinine levels increase especially during the first 24 weeks of therapy as do their weight and other markers of improved health. But there are others where this change may not be indicative of improved health and this is what we still need to explore and understand. As Drs Gupta and Currier said in closing comments, we need more prospective data. We need control groups and standardized definitions of kidney dysfunction and how best to measure it. We need to control for known kidney disease risk factors when we evaluate study populations. We need to understand the pathophysiology of why there may be kidney dysfunction. Until then, we need to continue to treat our patients with HIV using the available antiretroviral agents with care and caution. We need to monitor our patients not only for the known toxicities but for those for which we still are not aware. And it is important for patients to understand that their health care providers are ordering blood and urine tests not because the "doctors want to" but because it is the providers' responsibility for making sure patients are as safe as possible on all the medications they prescribe and that they can identify and remove harmful agents if possible.
The following studies were discussed and my comments follow each investigators'conclusions:
Poster 777: Differences in Calculated Glomerular Filtration Rates in Efavirenz- or Tenofovir-treated Adults in ESS40006
ESS40006 was primarily designed to compare 2 regimens of amprenavir/ritonavir (APV/r) (600/100 vs 900/100 twice daily) in subjects failing their current ART regimen. In addition, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive subjects were assigned to receive efavirenz (EFV), abacavir (ABC), and 1 additional NRTI, while NNRTI-experienced subjects were assigned to receive TDF in place of EFV. Descriptive statistics were summarized for subjects treated with EFV or TDF. The modification of diet in renal disease (MDRD) formula was used to calculate GFR. Potential predictors of GFR decline over 48 weeks of therapy, including baseline demographic data, CDC HIV-1 classification, CD4+ cell count, plasma HIV-1 RNA, prior therapy, concurrent ART, weight, and clinical laboratory results were assessed using multiple regression analyses.
Results: The median calculated GFR at baseline was comparable between the 2 groups (EFV-treated subjects [n = 38], 107.36; TDF-treated subjects [n = 76], 108.24). However, there were statistically significant differences in the median change in calculated GFR between the EFV-treated and TDF-treated subjects (median change from baseline at 24 weeks was 12.66 vs -9.85 [p <0.001] and at 48 weeks: -0.37 vs -11.07 [p = 0.004]). In the TDF group, the median reduction in calculated GFR from baseline was also statistically significant at both weeks 24 (p <0.001) and 48 (p <0.001). The only predictor of a decline in GFR in the multivariable model after adjusting for baseline GFR was TDF use.
Conclusions: For NNRTI-experienced subjects treated with TDF in this study, a significant decline in the median calculated GFR was observed over 48 weeks of therapy. This decline was not seen in the NNRTI-naive subjects treated with EFV in the same study. TDF use was the only predictor of GFR decline using multiple regression analysis. The clinical significance of these changes in calculated GFR deserves further study. Comment: This was an observational, not randomized study. There were no discontinuations of TDF for kidney events. They also did not control for other kidney dysfunction risk factors such as HCV or hypertension. Of note, there was no continuing decline in kidney function after 24 weeks on TDF.
Poster 778: Tenofovir (TFV)-induced Nephrotoxicity in the First Year of Therapy
Methods: At the Atlanta VA Medical Center, 222 patients who had baseline and follow-up serum creatinine and phosphates were analyzed. Follow-up determinations were made during routine clinical follow-up at 6 weeks, and 3-, 6-, 9-, and 12-month intervals after initiation of TFV. Data on co-morbid conditions and concomitant medications was collected to determine risk factors associated with nephrotoxicity. Renal insufficiency was defined as a ≥50% decline in calculated creatinine clearance from baseline. Hypophosphatemia was defined as a single serum phosphate <2.0 mg/dL during the treatment period (Ed note from Jules: is a single serum phosphate lab value adequate to evaluate hypophosphatemia?). Additionally, a composite of nephrotoxicity including both groups was analyzed, as was time to each endpoint.
Results: At baseline, patients had normal renal functioning (mean baseline SrCr 0.99 (±0.31) mg/dL, mean baseline creatinine clearance 99 (±31.15) mL/min), were highly treatment experienced (only 8 treatment naive (4%)), and had an AIDS diagnosis (188 patients (84.6%)). During the first year of therapy, 38 patients (17.12%) developed nephrotoxicity with 9 (4%) specifically developing renal insufficiency and 29 (13%) hypophosphatemia. Renal insufficiency appeared to be a cumulative toxicity with 56% of these patients experiencing it after >6 months of TFV exposure. Hypophosphatemia appeared to be more of an acute issue with 66% of these patients experiencing this during the first 6 months of TFV. Treatment naive patients and those with a prior history of amphotericin B exposure were >3 times more likely to develop the composite endpoint of nephrotoxicity (p <0.03, for each). Injecting drug users (RR 3.94 [1.05 to 14.778], p = 0.0329) and treatment naive patients (RR 11.78 [3.49 to 39.69] p <0.0001) were more likely to specifically develop renal insufficiency (p = 0.0329).
Conclusions: The incidence of nephrotoxicity in our cohort during the first year of therapy was higher than previously reported in other cohorts. Treatment naive patients, injecting drug users, and patients with previous exposure to amphotericin B were all at increased risk for renal complications. Comment: As with other retrospective cohort studies, there was no comparison group. It is critical to have a control group especially with treatment naive patients as it is not unusual to see an increase in serum creatinine with weight gain and improved muscle mass. Not surprisingly, drugs like amphotericin B which is known to reduce the GFR by 40-60%, was associated with increased kidney toxicity. Of concern during the open microphone session was that some patients were still requiring phosphorous replacement suggesting irreversible damage to the kidney. Those patients warrant further study.
Poster 779: Renal Impairment Associated with the Use of Tenofovir
Methods: We used medical records of 11,362 HIV-infected persons receiving care in 10 U.S. cities during 2000-2003 from the CDC's Adult/Adolescent Spectrum of HIV Disease project. Patients without a history of glomerular filtration rate (GFR) <90 were included in the analysis. Logistic regression was used to evaluate the association of TDF prescription with any renal impairment (GFR <90 mL/min), mild renal impairment (GFR 60 to 89 mL/min), moderate renal impairment (GFR 30 to 59 mL/min), and severe renal impairment (GFR <30 mL/min), controlling for sex, age, race, hypertension, anemia, and CD4 count. GFR was estimated from creatinine measurements using the simplified modified diet in renal disease equation, which considers sex, age, race, and serum creatinine.
Results: Of 11,362 patients, 3986 (35.1%), 724 (6.4%), and 293 (2.6%) experienced mild, moderate, and severe renal impairment, respectively. Persons prescribed a TDF-containing regimen were more likely to have renal insufficiency (adjusted odds ratio [aOR] 1.6, 95%CI 1.5 to 1.8) compared with those not prescribed TDF. When considering the severity of renal impairment in separate, similarly controlled multivariate models, we found that prescribed TDF was associated with mild renal impairment (aOR 1.6, 95%CI 1.5 to 1.8) and with moderate renal impairment (aOR 1.5, 95%CI 1.1 to 1.9), but not with severe renal impairment (aOR 1.3, 95%CI 0.9 to 1.9) renal impairment. Low CD4 count, history of hypertension, and anemia were associated with increased risk of more severe renal impairment.
Conclusions: Our findings demonstrate that TDF is associated with mild and moderate renal impairment, after controlling for other important factors associated with decreased renal function. Physicians should monitor patients receiving TDF and consider that mild or moderate renal impairment may be drug-associated. Further research is needed to determine whether changing from TDF to a different antiretroviral agent in the setting of mild or moderate renal impairment is beneficial in terms of progression to severe renal impairment and long-term survival. Comment: The data presented was updated from the abstract submitted but the results essentially were similar. The predictors of developing kidney dysfunction included lower CD4+ T-cell counts (reference value CD4 was 350), hemoglobin less than 8, diabetes, hypertension and TDF. This also is an observational study. Of note, this study looks at data during a time period when TDF may not have been dose adjusted for those with known kidney dysfunction. In addition, subjects' kidney function was analyzed by categories of kidney dysfunction rather than a continuous variable. Reassuring was that they did not see TDF associated with severe kidney dysfunction.
Poster 780: Didanosine and Lower Baseline Body Weight Are Associated with Declining Renal Function among Patients Receiving Tenofovir
Methods: Between November 2001 and September, 2005, we conducted this observational cohort study of all HIV-infected patients receiving TDF in an urban HIV clinic population. Development of abnormal renal function was defined as an absolute glomerular filtration rate (GFR) ≥90 before initiation of TDF, and <90 at the last creatinine measurement on TDF. We used logistic regression analysis to examine factors associated with abnormal renal function, including ART medications, weight at initiation of TDF, weight change by last measurement on TDF, race, age, gender, CD4 count nadir, HIV-1 RNA level, hepatitis C virus (HCV) antibody, diabetes, and hypertension. We used the Cockcroft-Gault (CG) equation that incorporates body weight to calculate GFR because weight changes are common among HIV-infected patients. We also examined GFR using the modification of diet in renal disease (MDRD) equation.
Results: Among the 497 patients initiating TDF, 87 patients developed abnormal renal function, which was associated with didanosine (ddI) use (p = 0.009), lower baseline weight (p = 0.001), and older age (p = 0.009) compared with patients with normal renal function. 79 of 87 patients had a moderate decline in GFR (≦60). Of 87 patients, 8 had a severe decline in GFR (>80) that was associated with ritonavir-boosted regimens (p=0.03) containing either amprenavir (p=0.04) or lopinavir (p=0.009), and a trend toward ddI use (38% vs 15%, p = 0.09). After adjusting for other factors, ddI (OR 2.5, p = 0.02), lower baseline weight (OR 0.95/kg, p = 0.001), and increasing age (OR 1.07/year, p <0.002) were significantly associated with abnormal renal function. The results were unchanged when only patients with moderate abnormalities were examined; there were too few patients with severe abnormalities for separate analysis. When GFR was calculated using MDRD, fewer patients had abnormal renal function than when the CG equation was used.
Conclusions: Increased age, ddI use, and lower baseline weight are significantly associated with risk for renal impairment among patients receiving TDF. GFR results using the MDRD were inconsistent with those calculated using CG which points to the importance of weight in the measurement of GFR among HIV-infected patients. Our findings suggest there may be a moderate and severe category of renal abnormalities associated with TDF and that ritonavir may contribute to severe abnormalities. Comment: I admit I have a bias and conflict here. The presenter, Dr. Heidi Crane worked in my clinic at Washington University during her residency. Not that I take any personal credit for her career development, I just am always so happy to see how accomplished she has become. Dr. Crane looked at both categories of renal dysfunction as well as change over a continuum plus calculated creatinine clearance by both methods. Another poster (#570) demonstrated that lopinavir/ritonavir does inhibit clearance of TDF by about 16%. The question is whether or not that percentage is really clinically significant but nonetheless, does suggest there is a drug interaction. This may in part explain why Dr Crane's study noted diminished kidney function in those taking amprenavir or lopinavir/r with TDF. Of note, not all the patients on amprenavir were taking ritonavir so further study of potential PI-TDF interactions are warranted.
Poster 781: The Safety of Tenofovir DF for the Treatment of HIV Infection: The First 4 Years
Methods: Safety data were evaluated from compassionate use/expanded access programs (EAP) in the United States, Europe, Australia, and Canada, as well as from post-marketing safety reports received through April 30, 2005. Serious adverse events were tabulated, and serious adverse events of clinical importance were characterized. Serum creatinine and phosphates were collected in >1600 patients in the EAP program.
Results: Data were reviewed from 10,343 patients in EAP programs and spontaneous post-marketing safety reports representing 455,392 patient-years of exposure to TDF. Serious adverse events were reported by 631 patients (6 %) in the EAP programs (211 [2%] serious adverse events related), and no single type of serious adverse event was observed in >1% of patients. In the EAP program, the most common serious adverse events were pneumonia (0.63%), renal (0.57%), pancreatitis (0.47%), fever (0.40%), and bacterial infections (0.26%); related serious adverse events were pancreatitis (0.28%), renal (0.22%), fever (0.15%), pneumonia (0.14%), and diarrhea (0.09%). In the post-marketing safety database, the reporting rates were highest for renal, pancreatitis, lactic acidosis, hepatitis, and diarrhea. Serious renal serious adverse events in the EAP and post-marketing included renal failure (0.3% of patients; 0.50 cases/1000 patient-years, respectively) Fanconi/tubular disorder (0.05%; 0.43), and elevated serum creatinine (0.10%; 0.19). Risk factors for renal serious adverse events included concomitant nephrotoxic medications and low CD4 cell count. Grade 3 or 4 elevations in serum creatinine were reported for 0.3% of 1699 patients in the EAP program. For post-marketing renal serious adverse events with creatinine data, the median maximum serum creatinine was 2.3 mg/dL (IQR 4.0), and median time to resolution to grade 2 or less was 29.0 days (95%CI 17 to 45). Mitochondrial toxicity, neuropathy, and bone fractures were reported infrequently in the EAP (L0.1%) or post-marketing database.
Conclusions: Safety data received during the first 4 years of TDF use demonstrate that the drug is well tolerated in HIV patients. The pattern of serious adverse events, including renal events, are similar in the post-marketing and EAP databases. The incidence of serious renal serious adverse events was 0.57% among 10,695 patients in the EAP; risk factors included concomitant nephrotoxic medications and low CD4 cell count. Bone fractures, neuropathy, and mitochondrial toxicity were reported infrequently. Comment: There have not been reports of kidney dysfunction in the large prospective randomized clinical trials conducted by Gilead. One reason may be secondary to the entry criteria. Patients must have creatinine clearances greater than 50 or sometimes even over 80 to be eligible and concomitant use of other drugs toxic to the kidney were not allowed. This study evaluated patients who went on the expanded access program. Of note only 5 out of 2821 patients had abnormal serum creatinine levels at baseline. Although 10,343 patients enrolled in the expanded access program, follow up data was only available for 1699. Nevertheless, the review of this data was consistent with others. It is an uncommon event. TDF is associated with kidney disease in those given other drugs that adversely affect the kidney and advanced HIV disease. Much more work is needed to precisely understand who is at risk of developing kidney disease and to assure all measures are taken to avoid kidney toxicity.
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