Special Feature: Tenofovir — A New Antiretroviral Agent
Special Feature
Tenofovir—A New Antiretroviral Agent
By Stan Deresinski, MD, FACP, and Carol A. Kemper, MD, FACP
When tenofovir disoproxil fumarate (PMPA; VireadTM) received accelerated approval by the FDA on Oct. 26, 2001, it became the first available nucleotide analog reverse transcriptase inhibitor (NRTI) for the treatment of HIV-infected adults. This action by the FDA was largely based on the results of the 2 clinical trials summarized here.
Study 902
Study 901, a dose-escalation trial, had previously demonstrated a median decrease in HIV-RNA levels after 28 days of 1.57 log10 in ART-inexperienced subjects and 0.97 log10 in ART-experienced subjects with a 300-mg once daily dose. Study 902 then examined the 48-week safety of once daily doses of tenofovir of 75 mg, 150 mg, and 300 mg when added to baseline ART in patients on stable regimens with plasma HIV-1 RNA levels of 400 copies mL-100,000 copies/mL. The primary end point was the time-weighted average change from baseline in log10 copies/mL of plasma HIV-1 RNA (DAVG). The DAVG at week 24 in the patients receiving 300 mg tenofovir daily was -0.62 log10 copies/mL; the week 24 DAVG in placebo recipients was + 0.2 log10 copies/mL. Placebo recipients were crossed over after 24 weeks to receive 300 mg tenofovir once daily and the week 48 DAVG in all patients receiving this dose of drug was maintained at -0.62 log10. Changes in CD4 count favored tenofovir, but were quite small. All 3 doses of the drug studied were similarly well tolerated. The 96-week data were presented at the Buenos Aires Conference in July 2001; viral load decreases were maintained with few additional mutations noted.
Study 907
In a larger, Phase III trial (Study 907), 552 patients with viral loads of 400 copies/mL to 10,000 copies/mL were randomized (2:1) to add tenofovir, 300 mg q.d. or placebo, to their stable existing ART regimens, in a blinded fashion. Virus from 94% had one or more NRTI resistance-associated mutations at baseline, 48% had NNRTI mutations, and 58% had PI resistance-associated mutations. The calculated DAVG at all assessed time points, from week 2 through week 24, demonstrated statistical superiority of drug over placebo, with the week 24 DAVG for tenofovir recipients being 0.61 log10 compared to -0.03 log10 for placebo recipients (P < 0.001). Forty-two percent of those given tenofovir achieved viral loads at 24 weeks of < 400 copies/mL and 21% achieved viral loads < 50 copies/mL; the comparable results for placebo recipients were, respectively, 13% and 1%. The mean time-weighted average CD4 increase at 24 weeks was only 12 cells/mm3 (P = 0.0008 vs placebo).
Virology (See Table 1)
Virological experiments found that tenofovir remains active in vitro against recombinant mutant clones of HIV-1 expressing NRTI resistance-associated mutations including L74V (ddI), T69D (ddC), Q51M complex, and the ZDV-resistance associated mutations, D67N + K70R ± K219Q, and T215Y. Tenofovir activity was only minimally increased in the presence of M184V (3TC, abacavir) or T215Y + M184V). T69S double amino acid insertion mutants were resistant to tenofovir.
In Study 902, the presence at baseline of ZDV or thymidine analog mutations (TAM; see Table 2) resistance mutations (74% of patients) in RT codons 41, 67, 70, 210, 215, or 219 (mean of 2.8 mutations) did not appear to adversely affect the virological response to tenofovir administration. In fact, patients with the 3TC resistance mutation, M184V, had a mean 24-week DAVG 0.91 1og10 decrease in viral load, which may be comparable to the -0.61 log10 decrease for all tenofovir recipients.
Table 1 |
Mutations Associated with Reduced in vivo Response to Tenofovir* |
|
Mutation |
L74V/I |
K65R |
> 3 TAMs** + M41L |
> 3 TAMS + L210W |
T69S |
*No response in 2 patients each with Q151M resistance complex and T69S in Study 907. |
**Thymidine-associated mutations (M41L, D67N, K70R, L210W, T215Y/F, and K219Q). |
|
Table 2 | ||
Pharmacokinetic Parameters and Dosing | ||
|
||
Protein binding | ||
Plasma: < 0.7% | ||
Serum: 7.2% | ||
Oral bioavailability—not affected by repeat dosing | ||
Fasting: 25% | ||
Cmax (300 mg dose) 240 ng/mL | ||
Tmax 0.51.0 hours | ||
High fat meal 39% | ||
Cmax increased ~14% (to 326 ± 119 ng/mL) | ||
AUC increased ~40% (to 3324 ± 1370 ng*h/mL) | ||
Tmax "delayed by 0.8 to 1.2 hours" | ||
Vdss 1.2 ± 0.4 L/kg | ||
|
||
No significant interaction with CYP450 isoforms CYP3A4, CYP2D6, CYP2C9, CYP2E1; 6% reduction in metabolism of CYP1A substrate | ||
Eliminated by glomerular filtration and tubular secretion | ||
No data in patients with hepatic or renal impairment | ||
PK drug-drug interactions: Increase dd + AUC + Cmax | ||
Adult dosing: 300 mg q.d. with food (~7001000 kcal containing 40-50% fat) 2 hours before or 1 hour after ddI. | ||
|
Phenotypic analyses at baseline found that 4 of 53 patients had > 4-fold reduced susceptibility to tenofovir and, as a group, these subjects did not respond to tenofovir therapy. All patients with baseline tenofovir susceptibility within 3-fold of wild-type virus had > 0.5 log10 decreases in viral load sustained through week 48, as did most within 4-fold of wild type.
Fourteen percent of placebo recipients and 22% of tenofovir 300 mg daily recipients developed an NRTI-associated RT mutation during Study 902. These mutations did not appear to blunt the virological response since the viral load decrease at 24 and at 48 weeks was virtually identical in this subset compared to the group of tenofovir 300 mg daily recipients as a whole. Four patients (2%) had selection of a K65R mutation, an alteration that has been associated with ddC, ddI, and abacavir use in vivo and by tenofovir in vitro. Three were taking, in addition to tenofovir, ddI or abacavir. Phenotypic analysis demonstrated that the K65R mutation was associated with a 2.8-3.9-fold reduction in tenofovir susceptibility.
The virologic substudy of Study 907 confirmed, in a small number of patients, a lack of response to tenofovir in the presence of the K65R mutation at baseline and also demonstrated a lack of response in 2 patients each with the multinucleoside Q151M resistance complex and the T69S double-insertion mutation. In Study 907, NRTI-associated mutations arose during therapy in 15% of tenofovir and 22% of placebo recipients, while NNRTI-associated mutation became apparent in 5% vs. 9%, respectively. While neither of these comparisons achieved statistical significance, significantly fewer tenofovir recipients developed PI-associated mutations than did placebo recipients (2% vs 8%, P = 0.02). Thus, the improved suppression of viral replication in the tenofovir recipients appeared to suppress the emergence of mutants with resistance to all 3 classes of antiretroviral drugs.
As in Study 902, patients in Study 907 whose virus developed NRTI-associated mutations had viral load suppression to 48 weeks similar in degree to the tenofovir group as a whole. The development of the K65R mutation, which occurred in only 3% of tenofovir recipients, was associated with a highly variable virological response (range, -1.10 log10 to +0.72 log10). Patients with baseline phenotypic > 4-fold reduced susceptibility to tenofovir at baseline did not, as a group, respond to therapy with this drug.
In addition, the virus from 90% of these patients failing ART-experienced patients were phenotypically susceptible to tenofovir at baseline. Phenotypic studies also found that patients whose virus had as much as 10-fold resistance to ZDV and/or > 30-fold resistance to 3TC responded to tenofovir. Diminished response to tenofovir was found in patients whose virus exhibited > 4-fold reduced susceptibility to this drug at baseline. This phenotypic and clinical resistance was associated with either the K65R mutation, a T69S double-insertion mutation, or the T215Y/F and multiple (mean 4.8) other NRTI resistance mutations at baseline. The K65R mutation arose during therapy in only 2.4% of tenofovir recipients. The development of resistance to tenofovir during therapy was infrequent and tenofovir therapy was associated with reduced development of mutations associated with resistance to all 3 classes of antiretrovirals.
Tolerability
Tenofovir was well tolerated through at least 48 weeks of administration, with only 5% of recipients discontinuing study treatment due to adverse events, the most frequent of which was nausea, resulting in discontinuation in 1% of patients discontinuing tenofovir. Cough also occurred more frequently in tenofovir 300 mg recipients than in placebo recipients (9% vs 4%; P = 0.0226). Taking into account all reported adverse events, vomiting occurred in 9% of tenofovir 300 mg q.d. recipients and in only 6% of placebo recipients (P = 0.0225). One percent discontinued tenofovir due to laboratory abnormalities. Three percent of patients developed serum creatinines > 1.5 mg/dL, but the maximum reached was only 1.9 mg/dL. Mild hypophosphatemia occurred in 15% of all tenofovir recipients with grade 3 or 4 abnormalities occurring in 4 patients, the lowest value reached being 1.5 mg/dL The incidence of fractures, all of which were trauma-induced, was lower in the tenofovir recipients than in the placebo recipients.
Comment
Upon absorption from the gastrointestinal tract, tenofovir disoproxil fumarate is rapidly converted by diester hydrolysis to tenofovir and, upon entering cells, is phosphorylated to the active metabolite, tenofovir diphosphate. In addition to competitively inhibiting viral RT, the active intracellular form competes with dATP for incorporation into nascent DNA and, lacking a 3¹ hydroxyl group, causes premature DNA chain termination. The drug is highly active in vitro against both HIV-1 and HIV-2, as well as against hepatitis B virus (including lamivudine-resistant strains). Tenofovir is reported to demonstrate strong in vitro synergy with ZDV, amprenavir, and all NRTIs, as well as minor to moderate synergy with ddI and nelfinavir. Although synergy was found in vitro with hydroxyurea, a clinical trial failed to confirm this finding in vivo.1 Antagonism has not been detected. Tenofovir is a weak inhibitor of mammalian DNA polymerases a, b, and g.
The oral bioavailability of tenofovir is 25% in fasted subjects, but is enhanced by administration with a high fat meal, a condition that increases the Cmax by approximately 14% and the AUC by approximately 40%.2). Tenofovir is predominantly excreted as unchanged drug by the kidneys with a significant contribution from tubular secretion. The terminal elimination half-life in plasma is 11-14 hours and the intracellular half-life is also prolonged, factors that allow once daily dosing. Clinically significant drug-drug pharmacokinetic interactions with most other antiretrovirals have not been detected. However, coadministration with buffered ddI resulted in a decrease in ddI Cmax by 28% and of AUC by 44%. As a consequence of the latter observation, tenofovir should be administered 2 hours before or 1 hour after administration of ddI.
Pharmacokinetic data in patients with renal insufficiency are not yet available, but dose adjustments are likely to be necessary. While there is also no data in patients with hepatic impairment, this is unlikely to affect tenofovir disposition since the drug is not metabolized by hepatic enzymes.
The limited CD4 increase seen in these tenofovir intensification studies are similar to the results seen in studies in which abacavir was added to failing background therapy in which, in a less ART-experienced group of patients, the CD4 increase at week 16 was 30 cells/mm3 and did not significantly differ from placebo.3 Viral load changes in abacavir recipients in that study were also similar to those seen in Study 907 in tenofovir recipients.
The presence of the K65R mutation at baseline is associated with a 3-4-fold reduction in in vitro susceptibility to tenofovir and with a reduced virological response to treatment with this drug. Since K65R, a mutation that also arose in a small number of patients during therapy tenofovir, is also associated with the use ddI, ddC, or abacavir, cross-resistance is a possibility. The T69S double-insertion mutation is also associated with reduced tenofovir susceptibility. Reduced responses to tenofovir were seen in patients whose virus had 3 or more ZDV-associated mutations together with either the M41L or the L210W mutation. The presence, individually, of D67N, K70R, T215Y/F, or K219Q/E/N did not appear to affect the response to tenofovir.
Overall, analysis of the compiled data indicates that durable viral load responses were achieved despite the presence, at baseline, of ZDV/TAM resistance mutations, the M184V 3TC mutation, and the T215Y "high level" ZDV resistance mutation, as well as in patients whose virus had NNRTI and/or PI-associated mutations. Tenofovir is also less susceptible to removal from viral DNA by pyrophosphorylsis or by nucleotide-dependent chain-terminator removal than either ZDV or d4T, possibly also accounting for lesser cross-resistance with these NRTIs.4 Reduced responses were noted in patients whose virus had either an M41L or L210W mutation in combination with at least 3 other TAMs. The K65R mutation is also associated with a reduced virological response to tenofovir.
Tenofovir is the "offspring" of adefovir, a nucelotide analog that is no longer undergoing development for the treatment of HIV infection, largely as the consequence of adverse effects on bone metabolism and kidney function. (Adefovir is undergoing evaluation—with use of a much lower dose—in the treatment of chronic hepatitis B virus infection.) Preclinical studies found that tenofovir causes reversible osteomalacia, associated with hypophosphatemia and phosphaturia, in newborn and juvenile monkeys dosed at 25 times the human exposure. Studies in other species indicate this is the result of inhibition of NaPi cotransporters in intestinal mucosa resulting in decreased PO4 absorption and in renal tubules resulting in decreased PO4 reabsorption. However, clinical trial results to date indicate that tenofovir, at a dose of 300 mg daily, does not exhibit similar toxicity when administered for as long as 48 weeks. Whether such toxicity will emerge with more prolonged use of the drug will be determined by continued clinical trials and by clinical experience. Its use in patients with chronic renal insufficiency, a group predisposed to osteomalacia, will need to be carefully observed.
Close observation may also be required in patients with chronic hepatitis B virus (HBV) coinfection. The activity of tenofovir against this hepadnavirus raises concern about the possibility that hepatitis flares may occur in coinfected patients who discontinue tenofovir, a concern that also exists with lamivudine withdrawal.
Thus, tenofovir appears safe and effective when added to virologically failing antiretroviral therapy for 48 weeks in patients with plasma HIV RNA concentrations less than 100,000 copies/mL. Genotypic and phenotypic data suggest the potential, in some instances, for cross resistance between tenofovir and abacavir, ddI, d4T, ddC, and ZDV. Cross resistance was not observed between tenofovir and 3TC. With the exception of K65R, RT mutations that occurred during therapy may be due not to tenofovir exposure, but to background antiretroviral therapy. In addition to its therapeutic activity, tenofovir may prove an especially effective component of postexposure prophylaxis.5 We look forward to the further data from these and further clinical trials. Two additional studies will be performed to achieve full, traditional approval of tenofovir. Tenofovir or placebo will be added to background therapy in pediatric patients while in an adult study ART-naïve patients will be given 3TC and efavirenz and randomized to also receive either tenofovir or d4T.
References
1. Deeks SG, et al. Hydroxyurea does not enhance the anti-HIV activity of low-dose tenofovir disoproxil fumarate. J Acquir Immune Defic Syndr. 2001;28: 336-339.
2. Barditch-Crovo P, et al. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2001;45:2733-2739.
3. Katlama C, et al. The role of abacavir (ABC, 1592) in antiretroviral therapy-experienced patients: results from a randomized, double-blind, trial. CNA3002 European Study Team. AIDS. 2000;14:781-789.
4. Naeger LK, et al. Tenofovir (PMPA) is less susceptible to pyrophosphorolysis and nucleotide-dependent chain-terminator removal than zidovudine or stavudine. Nucelosides Nucleotides Nucleic Acids. 2001; 20:635-639.
5. Van Rompay KK, et al. Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. J Infect Dis. 2001;184: 429-438.
Dr. Deresinski, Clinical Professor of Medicine, Stanford; Director, AIDS Community Research Consortium; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert. Dr. Kemper, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor of Infectious Disease Alert.
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