Tenofovir (Viread)

 

 

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Tenofovir (Viread)

Susa Coffey, MD

October 2, 2001; Updated November 25, 2008

Back to Drug Profiles Class Background U.S. Manufacturer Approval Generic Approval Formulation and Dosing Clinical Use Combinations Use in Initial vs Subsequent Therapy Factors Affecting Adherence Resistance Implications of tenofovir resistance for treatment with other antiretrovirals Implications of resistance to other antiretrovirals for treatment with tenofovir Special Uses Treatment of hepatitis B References Related Resources DHHS Guidelines Characteristics of NRTIs Drug Interactions with NRTIs Adverse Events of ARVs Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing) Interactions Database Stanford Resistance Figures/Notes Drug Labeling (Package Insert) Tenofovir (Viread, PMPA) FTC/TDF (Truvada) EFV/FTC/TDF (Atripla)

Class Adenosine nucleotide analogue Background U.S. Manufacturer Gilead Sciences Approval Tenofovir was approved by the FDA in 2001 for use in combination with other antiretroviral agents in adults with HIV infection. This recommendation was based primarily on a randomized, placebo-controlled study of HIV treatment-experienced individuals with detectable viral load on stable combination antiretroviral therapy. The addition of tenofovir to the existing regimen resulted in a significant decrease in viral load at week 24 of the study (0.61 log10 average decrease in viral load from baseline, compared with 0.03 log10 decrease in the placebo group; p < .0001). An increase in CD4 count of 12.6 cells/µL was seen in the tenofovir group, compared with a decrease of 10.6 cells/µL in the placebo group (p = .0008).(1) Generic Approval The FDA has granted a generic version of tenofovir "tentative approval" status for purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries. For a table of FDA-approved drugs for use under PEPFAR, see HIV InSite's PEPFAR overview. Formulation and Dosing Tenofovir is available in tablet form. It is approved for once-daily dosing. Tenofovir is available in combination with emtricitabine as a single tablet (Truvada). Tenofovir is also available in combination with emtricitabine and efavirenz as a single tablet (Atripla).   Dosing of Tenofovir Adult 300 mg QD Pediatric Not FDA approved in patients <18 years; under investigation Key to abbreviations: QD, once daily.   There are no food restrictions. Dosage adjustment is recommended in renal insufficiency. Tenofovir interacts with the antiretroviral medications didanosine and atazanavir; see Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for the tenofovir/didanosine interaction and tenofovir/atazanavir interaction. Please consult product labeling for detailed dosing information. FDA Pregnancy Category B. Clinical Use Combinations A direct comparison of tenofovir + lamivudine + efavirenz vs stavudine + lamivudine + efavirenz as initial therapy in antiretroviral-naive patients found the two treatments achieved similar rates of viral suppression, with 87% of participants in each arm having viral loads <400 copies/mL and 81% in each arm having viral loads <50 copies/mL at week 48 (intention-to-treat analysis, with missing values counted as treatment failure).(2) A 48-week comparison of tenofovir + emtricitabine with zidovudine + lamivudine, each in combination with efavirenz in previously untreated patients, found higher rates of virologic suppression in the tenofovir + emtricitabine group (HIV RNA <50 copies/mL in 80% vs 70%; p = .02), as well as greater increases in CD4 cell counts, and lower rates of treatment-limiting adverse effects.(3) Several triple-nucleoside regimens containing tenofovir have shown high rates of virologic failure in previously untreated individuals. Three studies of the triple-nucleoside analogue combination of tenofovir + abacavir + lamivudine (with all drugs dosed once daily) have shown early virologic failure in up to 50% of patients.(4,5,6) A study of tenofovir + didanosine + lamivudine showed virologic failure in 91% of patients at week 12.(7) The reasons for poor virologic response to these combinations are not yet known; pending further study, these triple-nucleoside regimens should be avoided. The combination of tenofovir + didanosine + efavirenz has demonstrated high rates of early virologic failure in treatment-naive individuals with high HIV RNA and low CD4 levels at baseline.(8,9) It is not yet known why this regimen resulted in high failure rates; pending further investigation, this combination should be used with caution. Coadministration of tenofovir with didanosine increases serum didanosine levels; dose-reduction of didanosine is recommended.(10) Coadministration of tenofovir with atazanavir lowers serum atazanavir levels and increases tenofovir levels (11); boosting atazanavir with low-dose ritonavir is recommended. Use in Initial vs Subsequent Therapy Treatment guidelines of the U.S. Department of Health and Human Services designate tenofovir + lamivudine or emtricitabine as the "preferred" dual-nucleoside backbone for use in initial therapy. The effectiveness of tenofovir in treatment-experienced patients with detectable viral loads suggests an important role in subsequent therapy. However, convenient dosing and low rate of known side effects make the drug attractive for use in initial regimens as well. Whether tenofovir is better used in initial or subsequent regimens is likely to depend on the individual case. Factors Affecting Adherence In the Phase III study described above,(1) the addition of tenofovir did not result in an increased rate of severe side effects, severe laboratory abnormalities, or drug discontinuation compared with placebo over 24 weeks. Of note, serious elevations in serum creatinine and decreases in serum phosphate levels, which were frequently observed in HIV trials of the related experimental drug adefovir dipivoxil, do not appear to be associated with tenofovir, even after 2 years of treatment.(12,13) However, cases of renal impairment associated with the use of tenofovir, including cases of acute renal failure and Fanconi syndrome, have been reported.(14) There is evidence that nucleoside analogues may be associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis and disorders of lipid metabolism.(15) However, studies of the relative effects of tenofovir on HIV reverse transcriptase and mitochondrial DNA polymerase suggest that the rate of mitchodrial toxicity is likely to be relatively low.(16) In a clinical comparison, tenofovir + lamivudine + efavirenz was associated with a lower rate of toxicities attributable to mitochondrial dysfunction (lactic acidosis, peripheral neuropathy, and lipodystrophy) than stavudine + lamivudine + efavirenz.(17) Resistance Resistance to tenofovir is associated with the selection of 1 or more of several resistance mutations. Implications of tenofovir resistance for treatment with other antiretrovirals The K65R mutation, associated with low-grade resistance to didanosine and abacavir, and moderate resistance to lamivudine, is selected by tenofovir in vitro but was found to occur infrequently in patients treated with tenofovir.(18) Implications of resistance to other antiretrovirals for treatment with tenofovir The presence of the lamivudine-associated M184V reverse transcriptase mutation does not reduce sensitivity to tenofovir. Single and some double thymidine analogue resistance mutations do not appear to confer tenofovir resistance. Tenofovir is also active against multinucleoside-resistant HIV expressing the Q151M mutation.(19) However, in clinical trials, the presence of 3 or more thymidine analogue resistance mutations is associated with a decreased response to tenofovir, particularly if these mutations include M41L or L210W.(20) The T69S insertion mutations, associated with resistance to multiple nucleoside analogues, are associated with resistance to tenofovir as well. Tenofovir resistance conferred by the T69S mutation or by multiple thymidine analogue resistance mutations appears to be multiplied if the M184V mutation is replaced by wild-type.(21) The K65R mutation, which may be selected by prior nucleoside analogue therapy, is associated with a modest decrease in sensitivity to tenofovir.(22) Tenofovir should be considered in choosing therapy for individuals experiencing viral recurrence on prior regimens, but resistance testing may be helpful in assessing the utility of tenofovir in the individual situation. Special Uses Treatment of hepatitis B Tenofovir is active against hepatitis B virus. In small studies of patients coinfected with HIV and hepatitis B, addition of tenofovir has been associated with improvement in laboratory markers of hepatitis B progression.(23,24) This improvement appears to extend to patients with lamivudine-resistant hepatitis B. A small randomized, controlled comparison of tenofovir and adefovir in coinfected patients found that tenofovir was not inferior to adefovir in reducing hepatitis B DNA levels and had a similar safety profile.(25) Some patients have experienced exacerbations of hepatitis B upon discontinuation of tenofovir. In 2008, tenofovir was approved by the FDA for the treatment of hepatitis B. DHHS guidelines suggest inclusion of tenofovir plus either lamivudine or emtricitabine in the antiretroviral regimens of patients coinfected with HIV and hepatitis B who require treatment for their HIV infection. This will result in treatment of both HIV and hepatitis B infections. References 1.   Squires K, Pozniak AL, Pierone G Jr, Steinhart CR, Berger D, Bellos NC, Becker SL, Wulfsohn M, Miller MD, Toole JJ, Coakley DF, Cheng A; Study 907 Team. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med. 2003 Sep 2;139(5 Pt 1):313-20. 2.   Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ, Cheng AK; 903 Study Group.Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191-201. 3.   Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, Lu B, McColl D, Chuck S, Enejosa J, Toole JJ, Cheng AK; Study 934 Group. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19;354(3):251-60. 4.   Gallant JE, Rodriguez AE, Weinberg WG, Young B, Berger DS, Lim ML, Liao Q, Ross L, Johnson J, Shaefer MS; ESS30009 Study. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis. 2005 Dec 1;192(11):1921-30. 5.   Khanlou H, Yeh V, Guyer B, Farthing C. Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and tenofovir DF in treatment-naive HIV-infected patients. AIDS Patient Care STDS. 2005 Mar;19(3):135-40. 6.   Landman R, Descamps D, Peytavin G, Trylesinski A, Katlama C, Girard PM, Bonnet B, Yeni P, Bentata M, Michelet C, Benalycherif A, Brun Vezinet F, Miller MD, Flandre P; TONUS (IMEA 021) Study Group. Early virologic failure and rescue therapy of tenofovir, abacavir, and lamivudine for initial treatment of HIV-1 infection: TONUS study. HIV Clin Trials. 2005 Nov-Dec;6(6):291-301. 7.   Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment-naive, HIV-infected patients receiving a once-daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. 11th Conference on Retroviruses and Opportunistic Infections; San Francisco; February 8-11, 2004. Abstract 51. 8.   Podzamczer D, Ferrer E, Gatell JM, Niubo J, Dalmau D, Leon A, Knobel H, Polo C, Iniguez D, Ruiz I. Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther. 2005;10(1):171-7. 9.   Maitland D, Moyle G, Hand J, Mandalia S, Boffito M, Nelson M, Gazzard B. Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS. 2005 Jul 22;19(11):1183-8. 10.   Kearney BP, Sayre JR, Flaherty JF, Chen SS, Kaul S, Cheng AK. Drug-drug and drug-food interactions between tenofovir disoproxil fumarate and didanosine. J Clin Pharmacol. 2005 Dec;45(12):1360-7. 11.   Piketty C, Gerard L, Chazallon C, Marcelin AG, Clavel F, Taburet AM, Calvez V, Madelaine-Chambrin I, Molina JM, Aboulker JP, Girard PM; Agence Nationale de Recherche sur le SIDA 107-Puzzle 2 Study Group. Salvage therapy with atazanavir/ritonavir combined to tenofovir in HIV-infected patients with multiple treatment failures: randomized ANRS 107 trial. 12.   Schooley RT, Ruane P, Myers RA, Beall G, Lampiris H, Berger D, Chen SS, Miller MD, Isaacson E, Cheng AK; Study 902 Team. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS. 2002 Jun 14;16(9):1257-63. 13.   Izzedine H, Hulot JS, Vittecoq D, Gallant JE, Staszewski S, Launay-Vacher V, Cheng A, Deray G; 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. 2005 Apr;20(4):743-6. 14.   Peyriere H, Reynes J, Rouanet I, Daniel N, de Boever CM, Mauboussin JM, Leray H, Moachon L, Vincent D, Salmon-Ceron D. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr. 2004 Mar 1;35(3):269-73. 15.   Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther 2000;22:911-36; discussion 898. 16.   Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, Anderson KS, Johnson KA. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 2001; 276:40847-57. 17.   Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ, Cheng AK; 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191-201. 18.   McColl DJ, Margot NA, Wulfsohn M, Coakley DF, Cheng AK, Miller MD. Patterns of resistance emerging in HIV-1 from antiretroviral-experienced patients undergoing intensification therapy with tenofovir disoproxil fumarate. J Acquir Immune Defic Syndr. 2004 Nov 1;37(3):1340-50. 19.   Miller MD, Margot NA, Hertogs K, Larder B, Miller V. Antiviral activity of tenofovir (PMPA) against nucleoside-resistant clinical HIV samples. Nucleosides Nucleotides Nucleic Acids 2001;20:1025-8. 20.   Margot NA, Isaacson E, McGowan I, Cheng A, Miller MD. Extended treatment with tenofovir disoproxil fumarate in treatment-experienced HIV-1-infected patients: genotypic, phenotypic, and rebound analyses. J Acquir Immune Defic Syndr. 2003 May 1;33(1):15-21. 21.   Miller MD, Margot NA, Lamy PD, Fuller MD, Anton KE, Mulato AS, Cherrington JM. Adefovir and tenofovir susceptibilities of HIV-1 after 24 to 48 weeks of adefovir dipivoxil therapy: genotypic and phenotypic analyses of study GS-96-408. J Acquir Immune Defic Syndr 2001;27:450-8. 22.   Wainberg MA, Miller MD, Quan Y, Salomon H, Mulato AS, Lamy PD, Margot NA, Anton KE, Cherrington JM. In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antivir Ther 1999;4:87-94. 23.   Nelson M, Portsmouth S, Stebbing J, Atkins M, Barr A, Matthews G, Pillay D, Fisher M, Bower M, Gazzard B. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. AIDS. 2003 Jan 3;17(1):F7-F10. 24.   Ristig MB, Crippin J, Aberg JA, Powderly WG, Lisker-Melman M, Kessels L, Tebas P. Tenofovir Disoproxil Fumarate Therapy for Chronic Hepatitis B in Human Immunodeficiency Virus/Hepatitis B Virus-Coinfected Individuals for Whom Interferon-alpha and Lamivudine Therapy Have Failed. J Infect Dis. 2002 Dec 15;186(12):1844-7. 25.   Peters M, Anderson J, Lynch P, Jacobson J, Sherman K, Alston Smith B, Swindells S, Liu T, Johnson V, Pollard R, Rooney J, Polsky B, and AACTG 5127 team. Tenofovir Disoproxil Fumarate Is Not Inferior to Adefovir Dipivoxil for the Treatment of Hepatitis B Virus in Subjects Who Are Co-infected with HIV: Results of ACTG A5127. 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston. Abstract 124.