To the Editor:
Tenofovir disoproxil fumarate (TDF), the only nucleotide analogue reverse transcriptase inhibitor approved for the treatment of HIV-1 infection, has been effective as a part of highly active antiretroviral therapy in treatment-experienced and naive patients.1,2 TDF is mainly eliminated by glomerular filtration and active tubular secretion. As the EMEA Summary of Product Characteristics3 shows, the exposure to TDF increases in patients with renal dysfunction and, based on pharmacokinetic data,4 dosing-interval adjustment of the drug is required in all patients with creatinine clearance less than 50 mL/min. It has been recommended that the use of TDF should be avoided with concurrent use of nephrotoxic medicinal products secreted by the same renal transporter.5 Although TDF has shown a good renal safety profile in clinical trials, similar to that of placebo or other antiretroviral drugs such as stavudine,1,2,6 cases of renal dysfunction associated with TDF, including Fanconi syndrome, have been reported after TDF was granted approval for treatment of HIV-1 infection.7-9 Most of these cases occurred in patients with underlying systemic or renal disease in which the dose interval of TDF was not adjusted, or in patients taking concomitantly nephrotoxic agents.
Between September 2002 and September 2004, we conducted a prospective, observational, multicenter, switch study with the main objective of identifying the most frequently occurring nucleoside reverse transcriptase inhibitor (NRTI)-associated toxicities causing the involved NRTI withdrawal and assessing their evolution after TDF substitution for the offending drug (Recover Study). The study has been performed in 120 HIV-1 units at teaching hospitals across Spain.
According to the design of the Recover Study, adult HIV-1-infected patients, under stable highly active antiretroviral therapy for at least 6 months, who switched from a NRTI to TDF because of toxicity, were followed up through 48 weeks. No other drug substitution was allowed.10
In the Recover Study, clinical and laboratory NRTI-associated abnormalities that justified the switching in the routine clinical practice were followed-up. But also, all newly adverse events leading to treatment discontinuation during the scheduled 48 weeks follow-up period were collected and assessed. Special attention has been taken to new cases of TDF-associated renal impairment, to estimate the incidence of renal dysfunction related to TDF use, to assess the characteristics of patients experiencing this adverse event, and to evaluate their outcome after discontinuation of TDF.
We have available data of follow-up from 1286 patients (being required at least 1 follow-up visit after inclusion for evaluation) of the 1350 patients included in the cohort. Most were men (69.3%) with a mean age of 40.3 years old (range, 21.9-64.8). The main HIV-1 risk factor was intravenous drug abuse (49%), followed by unsafe heterosexual (25.8%), and homosexual (21.3%) contacts. Most of them were heavily pretreated patients (73.5% were at third line of therapy or higher) and the mean duration of previous antiretroviral therapy was 74 months (range, 6-156). The mean CD4 cell count at baseline was 514 cells/mm3 (SD, 299). Seven hundred eighty two patients (60.8%) were receiving a non-NRTI-based regimen and 429 patients (33.3%), a PI-based regimen at the time of occurrence of NRTI-related toxicities.
Lipoatrophy and peripheral neuropathy were the most frequent causes of NRTI substitution (43% and 12%, respectively). Regarding laboratory abnormalities, anemia was the most common reason (5.7%). Stavudine was the main NRTI associated with lipoatrophy (40%); stavudine and didanosine, with peripheral neuropathy (8% and 3.4% cases, respectively); and zidovudine, with anemia (5.4%).
During the 48-week follow-up period, only 5 patients (0.39%) experienced a renal dysfunction and discontinued TDF treatment. The main characteristics of these patients are shown in Table 1. Three patients were male, and more than half were at fourth line of treatment or higher at the study entry. All cases had renal predisposing factors for developing renal impairment at baseline, and 2 of 5 had prior chronic renal failure. Although the creatinine clearance (estimate by Cockcroft-Gault equation) was below 50mL/min in these 2 cases, TDF-dosing interval was not adjusted when it was prescribed. The median time of TDF exposure was 19 weeks (range, 16-37) at the moment of TDF discontinuation. The description, the action taken and outcome of each renal impairment case are also described in Table 1. All patients discontinued TDF after the development of the renal disorder. Four patients recovered uneventfully, 1 patient who had obstructive uropathy due to nephrolithiasis required surgery. One patient died of acute myocardial infarction 2 days after interrupting TDF.
In our cohort of 1286 highly treatment-experienced patients treated with TDF-containing regimens and followed-up through 48 weeks, the incidence of renal impairment leading to discontinuation of TDF was very low (0.39 per 100 patient-year) and reversible. This information is in agreement with previous published data on this matter, both in clinical trials and in observational cohorts.11,12
According to 2 randomized, double-blind clinical trials,14 tenofovir-related nephrotoxicity seems to be rare with an estimated risk of approximately 0.02% that was reversible after TDF discontinuation. However, it has been suggested that clinical trials do not represent "the real world" because patients with renal impairment or risk factors for renal insufficiency are usually excluded. For this reason, it is important to explore clinical cohorts. Data from the Johns Hopkins HIV-1 Clinical Cohort12 showed that TDF use was associated with a significantly greater decline in creatinine clearance compared with the decline associated with the use of alternative NRTIs, but there was no difference in the rate of treatment discontinuation between TDF-treated patients and NRTI-treated patients because of renal abnormalities (5.5% vs 6.7%). In addition, data from the Chelsea and Westminster cohort13 revealed that it is relatively common to find the presence of other risk factors of renal impairment, seen in our cohort. Published data from the HOPS Cohort14 show an 1% incidence of renal insufficiency in patients with didanosine combined with TDF regiments; in Recover, we have 358 patients with didanosine + TDF-based regimen who has reached 48 weeks; renal function remained normal in all this patients.
In conclusion, from our Spanish cohort of heavily pretreated patients, we found that the risk of developing nephrotoxicity related to TDF leading to its discontinuation is rare (0.39%) and usually occurs when other risk factors for renal dysfunction or previous renal impairment exist. In addition, it is important to highlight the need of assessing renal function before initiate treatment with TDF and of adjusting the dose interval in case of renal impairment.
Santiago Moreno, PhD*
Pere Domingo, PhD†
Rosario Palacios, PhD‡
Jesús Santos, PhD‡
Vicenç Falcó, MD§
Javier Murillas, MD∥
Vicente Estrada, MD¶
Javier Ena, MD**
and Maria Luisa Alvarez, MD††
For the Recover Study Group
*Hospital Ramón y Cajal, Madrid, Spain
†Hospital Santa Creu i Sant Pau
‡Hospital Virgen de la Victoria
§Hospital de Vall d'Hebrón
∥Hospital de Son Dureta
Palma de Mallorca, Spain
¶Hospital Clínico San Carlos
**Hospital Marina Baixa, Alicante, Spain
and ††Gilead Sciences, Madrid, Spain
1. Schooley RT, Ruane P, Myers RA, et al, Study 902 Team. Tenofovir DF in antiretroviral-experienced patients: results from a 48-weeks, randomized, double-blind study. AIDS
2. Gallant JE, Staszewski S, Pozniak AL, et al, 903 Study Group. Efficacy and safety of Tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA
4. Kearney BP, Liaw S, Yale K, et al. Pharmacokinetics following single dose administration of tenofovir DF in subjects with renal impairment. Presented as a poster at the 6th International Congress on Drug Therapy in HIV Infection, Glasgow, 2002. Poster P186.
5. Izzedine H, Launay-Vacher V, Deray G. Renal tubular transporters and antiviral drugs: an update. AIDS
6. Izzedine H, Hulot JS, Vittecoq D, et al, for the Study 903 Team. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naive HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrol Dial Transplant
7. Lee JC, Marosok RD. Acute tubular necrosis in a patient receiving tenofovir. AIDS
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11. Izzedine H, Isnard-Bagnis C, Hulot JS, et al. Renal safety of tenofovir in HIV treatment-experienced patients. AIDS
12. Gallant JE, Parish MA, Keruly JC, et al. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. CID
13. Jones R, Stebbing J, Nelson M, et al. Renal dysfunction with tenofovir disoproxil fumarate-containing highly antiretroviral therapy regimens is not observed more frequently. A cohort and case-control study. J Acquir Immune Defic Syndr
14. Young B, Baker R, Armon C, et al. and the HOPS investigators. Safety and tolerability of didanosine combined with tenofovir DF in HIV-1 infected persons. Presented as a poster at the XV International AIDS Conference, Bangkok, Thailand, July 11-16, 2004. Poster 5922.