Antiretroviral Therapy in HIV-infected Adults: Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)
Tenofovir
On October 26, 2001, tenofovir (Viread®, Gilead Sciences) became the first FDA-approved agent in the NtRTI class. The drug was the second of two agents in this class to be developed by Gilead. Adefovir dipivoxil, the other agent in this class then under investigation, is no longer under consideration as an anti-HIV agent following disappointing virologic and immunologic results and a high incidence of proximal renal tubular dysfunction in a comparison with placebo (17% vs. 0.4%, P < .0001). This class of drugs is similar to the NRTIs except for a structural difference relating to phosphorylation.
Tenofovir disoproxil fumarate (DF), an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate, is an oral prodrug of tenofovir. It is approved for use in the treatment of HIV-1 infection in combination with other antiretroviral drugs. Tenofovir DF undergoes initial diester hydrolysis for conversion to tenofovir and is then phosphory-lated to tenofovir diphosphate. It inhibits reverse transcriptase in a similar manner as the NRTIs and ultimately causes termination of the DNA chain.
The recommended adult dose of tenofovir is one 300-mg tablet given once daily.
Resistance
On the basis of limited data, baseline phenotypic resistance to tenofovir in therapy-experienced patients appears to be low. Development of the K65R mutation, occurring in approximately 3% of participants in current studies, results in decreased susceptibility to tenofovir.18,20 In 20 samples with multiple mutations associated with resistance to zidovudine canadian, a mean 3.1-fold increase in tenofovir IC50 was observed (range, 0.8-8.4). The K65R mutation is selected both in vitro and in vivo with Didanosine tablet (ddI), zalcitabine (ddC), and abacavir generic (ABC); therefore, some cross-resistance may occur among these drugs.
Patients taking tenofovir who expressed three or more ZDV-associated mutations, including either M41L or L210W, showed reduced responses, although HIV RNA suppression in the treatment group was still greater than that in the placebo group (-0.21 log10 copies/ml versus + 0.1 log10 copies/ml). The presence of the D67N, K70R, T215Y/F, or K219Q/E/N mutation did not alter patients’ responses to tenofovir therapy.
Warnings and Precautions
Tenofovir is contraindicated in patients with known hyper-sensitivity to the product or any of its components. As with the other NRTIs, its administration may be associated with lactic acidosis and severe hepatomegaly with steatosis. Because tenofovir is eliminated primarily by the kidney, it is not recommended in patients with renal insufficiency (i.e., a creatinine clearance below 60 ml/min). Large doses of tenofovir in animal toxicology studies have been associated with renal toxic-ity and osteomalacia. Clinical monitoring for bone and renal toxicity is recommended.
Adverse Effects
The most common adverse events in patients taking teno-fovir in conjunction with other antiretroviral agents have been nausea, diarrhea, asthenia, and headache. Fewer than 1% of patients discontinued participation in clinical trials of tenofovir because of gastrointestinal side effects. Grade 3 and 4 laboratory abnormalities were no more common among tenofovir-treated patients than among placebo-treated patients.
Drug Interactions
Because of the renal elimination of tenofovir, drugs that compete for active renal tubular secretion or reduce kidney function may increase serum concentrations of tenofovir or other drugs that are eliminated by the kidneys. Tenofovir’s drug interactions with ddI, Lamivudine generic (3TC) IDV, efivarenz (EFV) (Sustiva generic, Bristol-Myers Squibb), and lopinavir/rotinavir (LPV/RTV) (Kaletra®, Abbott) were studied in healthy volunteers. Although the AUC concentrations of tenofovir were unchanged by 3TC, ddI, IDV, and EFV, they were increased by 34% (range, 25%-44%) in patients who were concurrently receiving LPV/RTV. The AUC concentrations of LPV/RTV were reduced by 15% and 24%, respectively, with tenofovir. When administered with tenofovir, the AUC concentrations of ddI were increased by 44% (range, 31%-59%); the mechanism of this interaction is unknown.
It is recommended that tenofovir be administered two hours before or one hour after ddI therapy and that patients be monitored closely for ddI toxicity. ddI should be administered on an empty stomach; tenofovir is recommended with food. The dietary restrictions accompanying the concurrent use of these two drugs may adversely affect patients’ adherence because of the complexity of the regimen.
Pharmacokinetics
The pharmacokinetic properties of tenofovir are provided in Table 3.
Table 3 Pharmacokinetics of Tenofovir
| Bioavailability | 25% (oral) |
| Maximum concentration (ng/ml) | 296 + 90 |
| Volume of distribution (liters/kg) | 0.3 + 0.6 (1 mg/kg IV dose); 1.2 ± 0.4 (3 mg/kg IV dose) |
| Protein binding | 0.7%-7.2%* |
| Metabolism | In vitro studies indicate that neither teno-fovir disoproxil nor tenofovir is a substrate of CYP-450 enzymes. |
| Elimination | • After IV administration: 70% to 80% of
dose is recovered unchanged in urine within 72 hours of initial dose. • After multiple oral doses taken with meals: 32 + 10% of administered dose is found in urine within 24 hours. |
| * Tenofovir concentrations of 0.01 to 25 g/ml. CYP-450 = cytochrome P-450; IV= intravenous.
Adapted from product information for Viread® (tenofovir disoproxil fumarate). Gilead; October 2001.18 |
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Clinical Trials with Tenofovir
The FDA’s approval of tenofovir was based on two studies, 24 to 48 weeks in duration, in which the drug was added to a failing regimen. The lack of data in treatment-naive populations led to labeling information that recommended tenofovir for use only in patients with viral strains expected to be susceptible, as assessed by laboratory testing or treatment history. Studies in antiretroviral therapy-naive patients are currently in progress.
Study 907. Study 907 enrolled 550 treatment-experienced patients with detectable viremia in a 24-week, randomized, double-blind, placebo-controlled, multi-center study to evaluate the effect of adding tenofovir versus placebo to an existing antiretroviral regimen. At the baseline evaluation, the mean CD4 count was 426 (range, 23-1,385) cells/mm3 and the viral load was 2,340 (range, 50-75,900) copies/ml. The patients were predominantly white men with a mean age of 42 years, and the mean duration of prior therapy was 5.4 years. NRTI-associated mutations were found in 94% of evaluable patients (n = 253) at baseline. A total of 69% had generic zidovudine/thymidine analogue mutations, 68% had the 3TC-associated M184V mutation, and 45°% had both.
Results at 24 weeks showed a 0.6 log10 copies/ml reduction in HIV-1 RNA from baseline in the tenofovir group but no change in the placebo group (P < .0001). A reduction to fewer than 50 copies/ml of HIV RNA was achieved in 71 teno-fovir-treated patients (19%) and in only two placebo-treated patients (1%). The mean absolute CD4 count increased by 11 cells/mm3 in the tenofovir arm but decreased by five cells/mm3 in the placebo arm.
The discontinuation rate in both treatment groups was similar, documented at 3%, and was attributed to adverse events. One patient in the tenofovir group (and no patients receiving placebo) experienced a new Centers for Disease Control and Prevention (CDC) class C adverse drug event.
Study 902. The other trial responsible for the accelerated approval of tenofovir was a dose-ranging, double-blind, placebo-controlled study of 186 treatment-experienced patients randomly assigned to receive either placebo or tenofovir daily (75, 150, or 300 mg) in addition to their existing antiretroviral reg-imen. Placebo patients received tenofovir 300 mg once daily at week 24, and all patients were switched to 300 mg once daily at week 48. The mean baseline CD4 count was 374 (range, 9-1,240) cells/mm3, and the median HIV RNA was 5,010 (range, 52-575,000) copies/ml.
An interim analysis at 24 weeks showed a mean difference in HIV RNA from a baseline figure of -0.62 log10 copies/ml in patients receiving the 300-mg dose, compared with -0.36 log10 copies/ml for the 150-mg dose (P = .001), -0.27 log10 copies/ml for the 75-mg dose (P = .014) and +0.04 log10 copies/ml (P < .001) for placebo.21 In patients receiving 300 mg of tenofovir through weeks 48 and 72, the mean change in HIV RNA from baseline remained approximately -0.6 log10 copies/ml. FDA briefing documents indicated that the modest efficacy seen in these two trials might be attributed to the narrow study population of treatment-experienced individuals.
Study 903. This phase III, randomized, double-blind, mul-ticenter comparison study is being conducted to assess the efficacy of tenofovir in patients without previous treatment. This study is intended to evaluate the comparative efficacy of tenofovir, lamivudine canadian (3TC), and EFV with that of Stavudine generic (d4T), 3TC, and EFV.
