Adenosine nucleotide analogue
| Clinical Use|
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate tenofovir + emtricitabine as the dual-nucleoside backbone for use in all "preferred" regimens for initial therapy.
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 81% in each arm having viral loads of <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 of <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)
In another randomized study, treatment-naive patients were given tenofovir + emtricitabine or abacavir + lamivudine, in combination with either efavirenz or ritonavir-boosted atazanavir. In patients whose pretreatment HIV RNA levels were ≥100,000 copies/mL, significantly higher rates of early virologic failure occurred in abacavir + lamivudine recipients than in tenofovir + emtricitabine recipients.(4) In those with pretreatment HIV RNA of <100,000 copies/mL, rates of viral suppression were not statistically different in recipients of either nucleoside analogue pair, whether combined with efavirenz or atazanavir + ritonavir.(5)
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.(6,7) 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.(8,9,10) A study of tenofovir + didanosine + lamivudine showed virologic failure in 91% of patients at week 12.(11) The reasons for poor virologic response to these combinations are not yet known; pending further study, they should be avoided.
Tenofovir has an important role in subsequent therapy. It often retains some degree of activity against HIV strains with resistance to other analogues,(12) and often is used in treatment-experienced patients.
| Potential Adverse Effects|
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.
Tenofovir has been associated with renal impairment in some individuals.(13) Cases of acute renal failure and Fanconi syndrome have been reported,(14) but more common is slowly progressive kidney disease. The cause is not definitively known but appears to involve proximal tubular impairment. Two large studies of treatment of patients without renal dysfunction at baseline found no significant differences in renal function were observed between subjects who received tenofovir and those treated with comparator NRTIs through 144 weeks of treatment.(2,3,15) Another study found that coadministration of tenofovir with a protease inhibitor led to greater decreases in estimated glomerular filtration rate (GFR) than did other combinations.(16) Other risk factors appear to include preexisting kidney disease. Renal function should be assessed before treatment with tenofovir, and regular monitoring should be performed for patients receiving tenofovir.
There is evidence that tenofovir may be associated with decreases in bone mineral density (17); monitoring and management of this effect is not certain.
Nucleoside analogues may cause mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis, abnormalities of body fat distribution, and disorders of lipid metabolism.(18) However, studies of the relative effects of tenofovir on HIV reverse transcriptase and mitochondrial DNA polymerase suggest that the rate of mitochondrial toxicity is likely to be relatively low.(19) 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.(20) In the comparison of tenofovir + emtricitabine with abacavir + lamivudine, given with either efavirenz or atazanavir/ritonavir (see Use in Initial vs Subsequent Therapy), there was no significant difference in limb fat loss between groups at 96 weeks.(21)
| Interactions with Other Drugs|
Coadministration of tenofovir with didanosine increases serum didanosine levels; dosage reduction of didanosine is recommended.(22) Coadministration of tenofovir with atazanavir lowers serum atazanavir levels and increases tenofovir levels (23); boosting atazanavir with low-dose ritonavir is recommended.
Resistance to tenofovir is associated with the selection of one or more of several resistance mutations.
| Implications of tenofovir resistance for treatment with other antiretrovirals|
The K65R mutation, which may be selected by tenofovir, is associated with resistance to most other nucleoside analogues. Zidovudine, however, retains activity in the presence of this mutation.
| Implications of resistance to other antiretrovirals for treatment with tenofovir|
| Single and some double thymidine analogue resistance mutations do not appear to confer significant tenofovir resistance. 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.(24)|
|The presence of the M184V reverse transcriptase mutation, associated with resistance to lamivudine and emtricitabine, does not reduce sensitivity to tenofovir, and when it occurs with thymidine analogue mutations, it may increase the susceptibility of HIV to tenofovir.|
|The K65R mutation, which may be selected by prior nucleoside analogue therapy, is associated with a decrease in sensitivity to tenofovir. |
|The T69S insertion mutations, associated with resistance to multiple nucleoside analogues, are associated with resistance to tenofovir as well.|
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.(25,26) 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.(27) 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 recommend inclusion of tenofovir plus either lamivudine or emtricitabine in the antiretroviral regimens of patients coinfected with HIV and hepatitis B. This will result in treatment of both HIV and hepatitis B infections.
| Preexposure prophylaxis|
Several studies have shown that preexposure prophylaxis (PrEP) using the combination of oral tenofovir and emtricitabine, taken daily by HIV-uninfected individuals, can reduce the risk of sexual acquisition of HIV.(28,29,30) These studies, performed in men who have sex with men and in heterosexual men and women, found that infection risk was reduced by 44% to 73%. One of these studies also examined the effect of oral tenofovir alone; it was 62% protective.(29) Another study of a tenofovir vaginal gel found a reduction in HIV infection rates in high-risk heterosexual women.(31) However, in other studies of high-risk women, oral tenofovir + emtricitabine, oral tenofovir alone, and vaginal tenofovir have not shown protective effects.(32,33,34) The reasons for the varied study results are not yet clear, but may include differences in adherence (in the studies that showed protective benefit, effectiveness appeared to be strongly correlated with adherence), in tissue penetration of the medication, and in intracellular metabolism.
In 2012, the FDA approved the combination of oral tenofovir + emtricitabine for use as PrEP by adults at high risk of sexual acquisition of HIV. Prophylactic tenofovir + emtricitabine is intended only for those who are tested and confirmed to be HIV uninfected, and as one component in a comprehensive prevention strategy that includes other risk-reduction measures and adherence support. Regular ongoing HIV testing is required to identify persons who become infected with HIV while on prophylaxis; tenofovir + emtricitabine is not sufficient as treatment for established HIV infection, and in persons with HIV infection, its use risks the development of resistance to the antiretroviral agents.
For use as PrEP, tenofovir + emtricitabine is to be taken daily. Potential adverse effects of tenofovir used in HIV-uninfected persons, including possible risks to fetal development in women who become pregnant while taking PrEP, have not been fully studied; monitoring is recommended.
|| || Squires K, Pozniak AL, Pierone G Jr, et al; 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. |
|| || 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. 2004 Jul 14;292(2):191-201.|
|| || Gallant JE, DeJesus E, Arribas JR, et al; 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.|
|| || Sax PE, Tierney C, Collier AC, et al; AIDS Clinical Trials Group Study A5202 Team. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009 Dec 3;361(23):2230-40.|
|| || Daar ES, Tierney C, Fischl MA, et al; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1.Ann Intern Med. 2011 Apr 5;154(7):445-56.|
|| || Podzamczer D, Ferrer E, Gatell JM, et al. Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther. 2005;10(1):171-7.|
|| || Maitland D, Moyle G, Hand J, et al. 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.|
|| || Gallant JE, Rodriguez AE, Weinberg WG, et al; 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.|
|| || Khanlou H, Yeh V, Guyer B, et al. 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. |
|| || Landman R, Descamps D, Peytavin G, et al; 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.|
|| ||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. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 51.|
|| || Schooley RT, Ruane P, Myers RA, et al; 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.|
|| || Hall AM, Hendry BM, Nitsch D, et al. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis. 2011 May;57(5):773-80.|
|| || Peyriere H, Reynes J, Rouanet I, et al. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr. 2004 Mar 1;35(3):269-73.|
|| || Gallant JE, Winston JA, DeJesus E, et al. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS. 2008 Oct 18;22(16):2155-63.|
|| || Gallant JE, Moore RD. Renal function with use of a tenofovir-containing initial antiretroviral regimen.AIDS. 2009 Sep 24;23(15):1971-5.|
|| || McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011 Jun 15;203(12):1791-801.|
|| || Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther. 2000 Aug;22(8):911-36; discussion 898.|
|| || Johnson AA, Ray AS, Hanes J, et al. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem. 2001 Nov 2;276(44):40847-57.|
|| || 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. 2004 Jul 14;292(2):191-201. |
|| || McComsey GA, Daar ES, O'Riordan M, et al. Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group Study A5224s, a substudy of A5202. J Infect Dis. 2013 Feb;207(4):604-11.|
|| || Kearney BP, Sayre JR, Flaherty JF, et al. Drug-drug and drug-food interactions between tenofovir disoproxil fumarate and didanosine. J Clin Pharmacol. 2005 Dec;45(12):1360-7.|
|| || Piketty C, Gerard L, Chazallon C, et al; 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. Antivir Ther. 2006;11(2):213-21.|
|| || Margot NA, Isaacson E, McGowan I, et al. 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.|
|| || Nelson M, Portsmouth S, Stebbing J, et al. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. AIDS. 2003 Jan 3;17(1):F7-F10. |
|| || Ristig MB, Crippin J, Aberg JA, et al. 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. |
|| || Peters MG, Andersen J, Lynch P, et al; ACTG Protocol A5127 Team. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006 Nov;44(5):1110-6.|
|| || Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99.|
|| || Baeten JM, Donnell D, Ndase P, et al; PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012 Aug 2;367(5):399-410.|
|| || Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012 Aug 2;367(5):423-34.|
|| || Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010 Sep 3;329(5996):1168-74.|
|| || Van Damme L, Corneli A, Ahmed K, et al; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012 Aug 2;367(5):411-22.|
|| ||Microbicide Trials Network. [MTN press release.] VOICE HIV prevention trial discontinues tenofovir gel arm for futility. November 25, 2011. Available at http://www.fhi360.org/en/Research/Projects/FEM-PrEP.htm.|
|| ||Microbicide Trials Network. [MTN press release.] VOICE HIV prevention trial continues, but researchers suspend oral tenofovir arm because of futility. September 28, 2011. Available at http://www.fhi360.org/en/Research/Projects/FEM-PrEP.htm.|