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More Details on Renal and Bone Toxicity With Tenofovir
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Glasgow Meeting: Part 1
8th International Congress on Drug Therapy in HIV Infection
November 12-16, 2006, Glasgow
Mark Mascolini
Every 2 years a stout contingent of HIV clinicians endures Scotland's sodden climes to attend "the Glasgow meeting"--formally designated the International Congress on Drug Therapy in HIV Infection. In return they hear top-drawer HIV experts discourse on the latest topics of therapeutic interest and gather fresh data from clinical trials of antiretroviral therapy. This year's Glasgow edition featured a flurry of studies analyzing short- and long-term toxicity with tenofovir DF (TDF), most of them finding small reason for concern--as long as monitoring remains constant. One Canadian study offered a useful inquest into independent predictors of renal toxicity with this popular nucleotide analog.
Over the next 2 weeks check the NATAP site for reviews of Glasgow reports on first-line strategies (including new efavirenz-versus-lopinavir studies), salvage tactics, resistance rates, other side effects, and new antiretrovirals.
CD4s, ddI, female gender raise risk of tenofovir renal toxicity
Analysis of 1182 people beginning tenofovir DF (TDF) in British Columbia independently linked concomitant didanosine (ddI), lower pre-TDF CD4 count, and female gender with a bigger risk of higher creatinine levels [1]. Concomitant ddI, fewer CD4s, and antiretroviral experience predicted stopping TDF for any reason.
Marianne Harris and colleagues at the British Columbia Centre for Excellence in HIV/AIDS studied all HIV-infected people in the province who started TDF between January 2003 and May 2005 if they had at least one creatinine level measured before starting TDF and at least one level after starting and while still taking TDF. Follow-up ranged from 6 to 35 months with a median of 12.2 months. Study endpoints were a creatinine level during TDF therapy at least 1.3 times the pre-TDF level or stopping TDF for any reason.
Of the 1182 people studied, 84.6% were male, 22.4% had AIDS, 15.9% began TDF as part of their first regimen, 34.3% took ddI with TDF, and 81.8% took TDF with a ritonavir-boosted protease inhibitor (PI). Median age measured 42 years, and treatment-experienced people had taken antiretrovirals for a median 34.0 months. Median CD4 count measured 220 (interquartile range [IQR] 120 to 370), median viral load 24,500 copies (IQR <50 to >100,000 copies), median creatinine 83 micromol/L (IQR 72 to 92) (0.94 mg/dL), and median glomerular filtration rate 92.2 mL/min/73/m2) (IQR 80.5 to 105.7).
At the end of the median 1 year of follow-up, 62 people (7.5%) saw their creatinine jump 1.3 or more times above the pre-TDF level and 30 (4.3%) had two such jumps. While 236 people (20.0%) stopped TDF and/or other drugs in their regimen, 34 (3.2%) stopped only TDF. Sixty-six people (5.6%) died.
Univariate analysis tied seven factors to a creatinine rise of at least 30%: lower pre-TDF CD4 count (P < 0.0001), higher pre-TDF viral load (P = 0.0115), antiretroviral experience (P = 0.0359), female gender (P < 0.0001), concomitant ddI (P = 0.0065), concomitant ritonavir-boosted PI (P = 0.0542), and prior AIDS (P = 0.0552). In a multivariate analysis, three of these factors--ddI, lower baseline CD4 count, and female gender--independently raised the risk of one creatinine reading 1.3 times above baseline (Table 1). Lower pre-TDF CD4 count nearly doubled the risk of consecutive creatinine levels at least 1.3 times above baseline (adjusted odds ratio 1.92, 95% confidence interval [CI] 1.33 to 2.86, P = 0.0005).
Univariate analysis picked out five predictors of stopping TDF: lower pre-TDF CD4 count (P < 0.0001), higher pre-TDF viral load (P < 0.0001), antiretroviral experience (P < 0.0001), female gender (P = 0.0112), and concomitant ddI (P < 0.0001). Two of those factors--concomitant ddI and lower CD4 count--independently raised the risk of stopping TDF, while antiretroviral experience independently lowered the risk of stopping the drug (Table 2).
Harris noted several limitations of this analysis:
- The study was not designed to gauge the incidence of TDF-related clinical kidney problems.
- The British Columbia database did not include information on weight, race, history of kidney disease, concomitant nonantiretroviral drugs, or other conditions that may affect the kidney.
- The analysis did not include a statistical adjustment for TDF dose interval.
- Creatinine data were missing for 356 of 1182 people.
- Phosphorus data were missing for 1029 of 1182 people.
Because of the correlations between ddI plus TDF and creatinine jumps or TDF discontinuation, Harris postulated that mitochondrial toxicity may explain renal problems with TDF. Renal toxicity did not correlate with ritonavir-boosted PIs in these people, who primarily used ritonavir-boosted atazanavir.
Harris and colleagues did not report ddI dosing data on this cohort, but a Spanish group looking at 749 people who started TDF with ddI--80% of them with 250 mg of ddI--found no link between coadministration of the drugs and renal toxicity [2]. This retrospective analysis involved people who started a TDF/ddI regimen and either stayed with it through follow-up or switched the TDF or ddI for any reason besides virologic failure. The group's CD4 count averaged 412 (standard deviation 279). While 45.5% began TDF/ddI in a rescue regimen after virologic failure, 24.3% switched to a regimen including TDF/ddI to simplify their current regimen, and 4.1% included TDF and ddI in their first regimen.
After a median follow-up of 9.1 months, glomerular filtration rate (GFR) measured by the modification of diet in renal disease (MDRD) method did not change significantly. Creatinine levels averaged 0.89 mg/dL before people began TDF/ddI and did not change significantly through follow-up. After 943.1 person-years of follow-up, 5 people (0.7%) stopped treatment because of renal side effects; all had started ddI at the 250-mg dose.
Proteinuria screening advised for all people starting TDF
All 20 people in a London case series of renal toxicity during TDF therapy had proteinuria, and 19 of them (95%) had a drop in estimated GFR to less than 90 mL/min/173m2 [3]. Clare Davies and coworkers from London's Mortimer Market Centre and the Royal Free Hospital recommended that everyone starting TDF should have regular screening for proteinuria and that further tests for proximal tubule dysfunction should be considered for those with proteinuria.
All 20 patients were referred to an HIV renal clinic while taking TDF. They represented 1.4% of 1406 TDF-treated people in two London HIV clinics from 2004 into 2006. All were men, 19 were white, and their ages ranged from 27 to 59 years (median 45.7 years). Four had hypertension, 1 had hepatitis C virus coinfection, but none had diabetes. Nine men were taking other drugs that may cause kidney toxicity, including acyclovir by 4, cotrimoxazole by 4, and nonsteroidal antiinflammatories by 4. Only 1 of these 9 stopped the other drug when starting TDF.
The men had spent a median of 6.8 years on antiretroviral therapy, had taken a median of 3.8 antiretrovirals, and had taken TDF for a median of 2.3 years (range 0.2 to 4.2 years). Six men (30%) were taking their first antiretroviral regimen, 18 (90%) were taking a ritonavir-boosted PI (14 lopinavir/ritonavir), and 5 were taking ddI. Most men had well controlled HIV replication, and the median CD4 count stood at 501 (range 130 to 1116).
One man had acute renal failure and the other 19 had proteinuria when first evaluated at the HIV renal clinic. Among the 19 with proteinuria, 8 met criteria for diagnosis of Fanconi syndrome (hypophosphatemia, tubular proteinuria, and glycosuria). In the other 11 men the main reason Fanconi syndrome could not be confirmed was that appropriate tests were not done or not recorded.
Among 17 men with creatinine readings before starting TDF, all were within the normal range. Most of them had rising creatinine during TDF therapy, and those elevations fell in all but 1 person after TDF stopped. All men had an elevated urinary protein creatinine ratio while taking TDF, and all ratios fell significantly when they stopped the drug. None of 6 men who had their urinary albumin creatinine ratio measured had a ratio that could explain detectable proteinuria. Davies believes this finding indicates that the proteinuria was not largely glomerular in origin. In 10 men who had urinary retinol binding protein measured, all had increased excretion, a finding indicating proximal tubule dysfunction.
Among 17 men with alkaline phosphatase in the normal range before starting TDF, 16 had an increase after starting the drug, and 11 reached a level above the upper limit of normal. Alkaline phosphatase fell in 19 of 20 men after they stopped TDF. Among 14 men who had plasma phosphates measured before starting TDF, phosphates fell in all of them with the drug. Nineteen men (95%) had hypophosphatemia upon diagnosis of renal toxicity, and phosphates returned to normal in 17 after they stopped TDF. Bone scans confirmed osteomalacia in 7 of 12 men.
Davies and colleagues concluded that the clinical presentation of renal toxicity during TDF therapy may include renal dysfunction, Fanconi syndrome, or osteomalacia. They believe their findings "support proximal tubular toxicity as the common pathogenic mechanism" for renal toxicity in TDF-treated people. Although TDF-associated renal toxicity appears to be reversible, they added, long-term follow-up is essential.
TDF safety in people with mild renal impairment
Antiretroviral-naive people starting anti-HIV therapy with mild renal impairment or with conditions that may cause renal impairment had no more renal side effects on TDF through 96 weeks of follow-up than on a thymidine analog (stavudine [d4T] or zidovudine [AZT] [4]. That finding emerged from analysis of two trials randomizing previously untreated people to (1) TDF or d4T plus lamivudine (3TC) and efavirenz or (2) TDF or AZT plus 3TC and efavirenz. Schlomo Staszewski (J.W. Goethe University, Frankfurt) and colleagues in the US and UK focused on study participants with mild renal impairment, hypertension, and/or diabetes mellitus when they signed up for the trials.
The researchers defined mild renal impairment as an estimated GFR or 50 to 80 mL/min (0.83 to 1.33 mL/s) by the Cockroft-Gault method, and they rated people as hypertensive or diabetic if they were taking drugs for those conditions. Everyone in this analysis had a pretreatment viral load above 5000 copies/mL, no significant clinical or lab abnormalities beyond mild kidney impairment, a serum creatinine below 1.5 mg/dL (133 micromol/L), and a serum phosphorus at or above 2.2 mg/dL (0.71 micromol/L). Pretreatment demographics and renal values did not differ between people assigned to TDF and those assigned to d4T or AZT.
Serum creatinine fell significantly and estimated GFR rose significantly in the control group but not in the TDF group, while serum phosphorus fell significantly with TDF but not with AZT or d4T (Table 3). Only 1 person in the analysis--someone in the control groups--had confirmed renal toxicity after 96 weeks of follow-up (Table 3).
Among 161 people with fewer than 50 CD4 cells when they started therapy, median change from baseline in estimated GFR was not significant with TDF or with a thymidine analog. No one had to stop TDF in either trial because of clinical or laboratory renal abnormalities, and Fanconi syndrome did not develop in either study.
Kidney and bone safety with TDF: long-term follow-up
The Glasgow meeting offered two other analyses of kidney and bone toxicity in people starting TDF. Five-year follow-up of 86 previously untreated patients who enrolled in an extension of the TDF versus d4T trial (see previous section) had no significant changes in estimated GFR by either the Cockroft-Gault or MDRD method [5]. They did, however, have significant 5-year drops from baseline values in hip bone mineral density (-1.5%, P = 0.003) and spine bone mineral density (-2.7%, P < 0.001), though neither hip nor spine density fell in this group after the first year of TDF therapy.
By the Cockroft-Gault method median GFR rose from 116 mL/min at baseline to 122 mL/min at year 5, a nonsignificant change. By MDRD median GFR inched up from 112 mL/min/1.73m2 to 117 mL/min/1.73m2 over 5 years, also a nonsignificant drift. Two of 86 people (2%) had a confirmed grade 1 serum creatinine elevation of 1.5 to 2.0 mg/dL through 5 years; no one had a grade 2, 3, or 4 elevation. No one dropped out of the trial's extension phase because of kidney toxicity; 1 person quit because of an asymptomatic rise in serum amylase/lipase. Mean limb fat did not change from year 2 to year 5.
After 96 weeks of follow-up in a trial comparing TDF/emtricitabine (FTC) with AZT/3TC--both plus efavirenz--GFR did not differ significantly between the groups when measured by the Cockroft-Gault method [6]. But the MDRD method traced a 96-week drop in median GFR in the TDF/FTC group (110 to 100 mL/min/1.73m2) and a small rise in the AZT/3TC group (105 to 108 mL/min/1.73m2), a significant between-group difference (P = 0.006). No one dropped out of the trial because of renal toxicity. Total limb fat improved significantly with TDF/FTC (7.4 to 8.1 kg, P = 0.01) and fell significantly with AZT/3TC (6.0 to 5.5 kg, P = 0.001).
References
1. Harris M, Joy R, Zalunardo N, et al. Predictors of creatinine increase and drug discontinuation in patients receiving tenofovir DF. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow. Abstract PL13.2
2. Gutierrez F, Antela A, Jimenez F, et al. Renal safety profile of tenofovir plus didanosine containing regimens: results from the DIDITEN cohort. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow. Abstract P151.
3. Davies C, Hall AM, Williams I, et al. Tenofovir-associated renal toxicity. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow. Abstract P149.
4. Staszewski S, Pozniak A, Gallant J, et al. Renal safety profile of tenofovir DF (TDF)-containing compared to non-TDF-containing regimens in antiretroviral-naive patients with mild renal impairment or hypertension and/or diabetes mellitus. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow. Abstract P157.
5. Cassetti I, Madruga JVR, Suleiman JMAH, et al. The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 5 years in antiretroviral-naive patients. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow. Abstract P152.
6. Pozniak A, Gallant J, DeJesus E, et al. Efficacy and safety of tenofovir DF, emtricitabine and efavirenz (EFV) compared to fixed dose zidovudine/lamivudine and EFV through 96 weeks in antiretroviral treatment-naive patients. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow. Abstract P6.
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